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Posts Tagged ‘cystathionine beta synthase’


How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Curator: Larry H Bernstein, MD, FACP

The Open Clinical Chemistry Journal, 2011; 4: 34-44

http://occj.com/1874-2416/11 2011/
http://dx.doi.org/11.2011/occl/1874-2416/
Bentham Open   Open Access

Introduction:  The following document is a seminal article concerning the relationship between hyoerhomocysteinemia and cardiovascular and other diseases. It provides a new insight based on the metabolism of S8 and geographic factors affecting the distribution, the differences of plant and animal sources of dietary intake,
and the great impact on methylation reactions.  The result is the finding that hyperhomocysteine is a “signal”, just as CRP is a measure of IL-6, IL-1, TNFa -mediated inflammatory response.  A deficiency of S8 due to the unavailability of S8, leads to CVD, and is seen in sulfur deficient regions with inadequate soil content and with veganism.  Hyperhomocysteinemia is also an indicator of CVD risk in the well fed populations, and that gives us a good reason to ASK WHY?

I have trimmed the content to make the necessary points that would be sufficient for this content.  The article can be viewed at OCCJ online.

The Oxidative Stress of Hyperhomocysteinemia Results from Reduced Bioavailability of Sulfur-Containing Reductants

Yves Ingenbleek*
Laboratory of Nutrition, Faculty of Pharmacy, University Louis Pasteur Strasbourg, France

Abstract

A combination of subclinical malnutrition and S8-deficiency

  • maximizes the defective production of Cys, GSH and H2S reductants,
  • explaining persistence of unabated oxidative burden.

The clinical entity

  • increases the risk of developing cardiovascular diseases (CVD) and stroke
    • in underprivileged plant-eating populations
    • regardless of Framingham criteria and vitamin-B status.

Although unrecognized up to now,

  • the nutritional disorder is one of the commonest worldwide,
  • reaching top prevalence in populated regions of Southeastern Asia.

Increased risk of hyperhomocysteinemia and oxidative stress may also affect

  • individuals suffering from intestinal malabsorption or
  • westernized communities having adopted vegan dietary lifestyles.

Vegetarian subjects

  • consuming subnormal amounts of methionine (Met) are characterized by
  • subclinical protein malnutrition causing reduction in size of their lean body mass (LBM) best
  • identified by the serial measurement of plasma transthyretin (TTR).

As a result, the transsulfuration pathway is depressed at cystathionine-beta-synthase (CbS) level

  • triggering the upstream sequestration of homocysteine (Hcy) in biological fluids and
  • promoting its conversion to Met.

Maintenance of beneficial Met homeostasis is

  • counterpoised by the drop of cysteine (Cys) and glutathione (GSH) values downstream to
  • CbS causing in turn declining generation of hydrogen sulfide (H2S) from enzymatic sources.

The biogenesis of H2S via non-enzymatic reduction is further inhibited in areas where

  • earth’s crust is depleted in elemental sulfur (S8) and sulfate oxyanions.

Keywords: Vegetarianism, malnutrition, sulfur-deficiency, hyperhomocysteinemia, oxidative stress, hydrogen sulfide, cardiovascular diseases, developing countries, Asia.

Homocysteine (Hcy) Generated by Transmethylation Pathway and Degraded via Transsulfuration Pathway

Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid (SAA)

  • generated by the intrahepatic transmethylation (TM) of dietary Met.
  • It may either be recycled to Met following remethylation (RM) pathways or
  • catabolized along the transsulfuration (TS) cascade.

Under normal circumstances, the Met-Hcy cycle stands under the regulatory control of three water soluble B-vitamins:

  • folates (5-methyl-tetrahydrofolates, B9) are regarded as the main factor working as donor of the CH3 group involved in the remethylation process,
  • pyridoxine (pyridoxal-5’-phosphate, PLP, B6) plays the role of co-factor of both
  • cystathionase enzymes belonging to the TS pathway and cobalamins (B12) ensure that of methionine-synthase.

Met-Hcy-Met Cycle

The main steps of the Met _ Hcy _Met cycle are summarized in Fig. (1).

FIGURE 1 NR H2S

Fig. (1). Schematic representation of the methionine cycle and homocysteine degradation pathways.

Compounds: ATP, adenosyltriphosphate; THF, tetrahydrofolate; SAM, S- adenosylmethionine; SAH, adenosylhomocysteine; Cysta, cystathionine; Cys, cysteine;
GSH, glutathione; H2S, hydrogen sulfide; Tau, taurine; SO4-2 , sulfate oxyanions.
Enzymes: (1) Met-adenosyltransferase; (2) SAM-methyltransferases; (3) adenosyl-homocysteinase; (4) methylene-THF reductase; (5) Metsynthase; (6) cystathionine
-b-synthase
, CbS;  (7) cystathionine-b-lyase, CbL; (8) g-glutamyl-synthase; (9) g-glutamyl-transpeptidase; (10)oxidase; (11) reductase; (12) cysteine-dioxygenase, CDO.

Metabolic pathways

Met molecules supplied by dietary proteins are

  • submitted to TM processes
  • releasing Hcy which may in turn either
    • undergo Hcy_Met RM pathways or be
    • irreversibly committed into TS decay.

Impairment of CbS activity in protein malnutrition, entails

  • supranormal accumulation of Hcy in body fluids,
  • stimulation of (5) activity and maintenance of Met homeostasis.

This last beneficial effect is counteracted by

  • decreased concentration of most components generated downstream to CbS,
  • explaining the depressed CbS- and CbL-mediated enzymatic production of *H2S along the TS cascade.

The restricted dietary intake of elemental S is a limiting factor for

  • its non-enzymatic reduction to **H2S which contributes to
  • downsizing a common body pool (dotted circle).(Fig 1)

Combined protein- and S-deficiencies work in concert

  • to deplete Cys, GSH and H2S from their body reserves,
  • impeding these reducing molecules from countering
  • the oxidative stress imposed by hyperhomocysteinemia.

Hyperhomocysteinemia

Hyperhomocysteinemia (HHcy) is an acquired metabolic anomaly first identified by McCully [1]

The current consensus is that dietary deficiency in any of
three water soluble vitamins may operate as causal factor of HHcy.

  • PLP–deficiency may trigger the upstream accumulation of Hcy in biological fluids [2] whereas
  • the shortage of vitamins B9 or B12 is held responsible for its downstream sequestration [3,4].

HHcy is regarded as a major causal determinant of CVD

  1. working as an independent and graded risk factor
  2. unrelated to the classical Framingham criteria such as
  • hypercholesterolemia,
  • dyslipidemia,
  • sedentary lifestyle,
  • diabetes and
  • smoking.

Hcy may invade the intracellular space of many tissues and locally generate [5]

  • endothelial dysfunction working as early harbinger of blood vessel injuries and atherosclerosis.

Most investigators contend

  • that production of harmful reactive oxygen and nitrogen species (ROS, NOS), notably
    • hydrogen peroxide (H2O2), superoxide anion (O2 .-) and peroxinitrite (ONOO.-),
    • constitutes a major culprit in the development of HHcy-induced vascular damages [7-10].

Accumulation of ROS
associated with increased risk for

  • cardiovascular diseases [11]
  • stroke [12],
  • arterial hypertension [6],
  • kidney dysfunction [13],
  • Alzheimer’s disease [14],
  • cognitive deterioration [15],
  • inflammatory bowel disease [16] and
  • bone remodeling [17].

These effects overlook the protective roles played by

  • extra- and intracellular reductants such as cysteine (Cys) and glutathione (GSH)
    • in the sequence of events leading from HHcy to tissue damage.

Hydrogen Sulfide (H2S)

After the discovery of nitric oxide (NO) and carbon oxide (CO), hydrogen sulfide (H2S) is the

  • third gaseous signaling messenger found in mammalian tissues [18].

H2S is a reducing molecule displaying strong scavenging properties

  • as the gasotransmitter significantly attenuates [19, 20] or
  • even abolishes [21,22] the oxidative injury imposed by HHcy burden.

The endogenous production of the naturally occurring H2S reductant depends on

  • Cys bioavailability through
  • the mediation of TS enzymes [23,24].

H2S may also be produced in human tissues starting from elemental sulfur,

  • by a non-enzymatic reaction requiring the presence of Cys, GSH, and glucose [25,26].

It would be worth disentangling the respective roles played by

  1. Cys,
  2. GSH
  3. H2S
  • for the prevention and restoration of HHcy-induced oxidative lesions.
  •  but the plasma concentration of Cys and GSH is severely depressed in
  • subclinically malnourished HHcy patients [27],
    •  impeding appropriate biogenesis of H2S molecules.

The present paper reviews the biological consequences

  • resulting from the complex interplay existing between the 3 reducing molecules,
  • to gain insight into the pathophysiologic mechanisms associated with HHcy states.

CLINICAL BACKGROUND

Numerous surveys have conclusively shown that the water soluble vitamin deficiency concept,

  • provides only partial causal account of the HHcy metabolic anomaly.

The components of body composition, mainly

  • the size of lean body mass (LBM),
  • constitutes a critical determinant of HHcy status [28,29].

Because nitrogen (N) and sulfur (S) concentrations

  • maintain tightly correlated ratios in tissues, we hypothesize 
  • defective N intake and accretion rate would cause concomitant and
  • proportionate depletion of total body N (TBN) and total body S (TBS) stores [30].

Our clinical investigation undertaken in Central Africa in apparently healthy but

  • nevertheless subclinically malnourished vegetarian subjects has
  • documented that reduced size of LBM could lead to HHcy states [27].

The field study conducted in the Republic of Chad, populated by the Sara ethnic group [27], is a  semi-arid region and

  • the staple food consists mainly of cassava, sweet potatoes, beans, millets and groundnuts.

Participants were invited to fill in a detailed dietary questionnaire whose results were compared with values reported in food composition tables [32-34] [27].
The dietary inquiry indicates that participants

  • consumed a significantly lower mean SAA intake (10.4 mg.kg-1.d-1)[27]
  • than the Recommended Dietary Allowances (RDAs) (13 mg.kg-1.d-1)[33,34].

Blood Analytes

The blood lipid profiles of rural subjects were confined within normal ranges

  • ruling out this class of parameters as causal risk factors for CVD disorders.

The normal levels measured for pyridoxine, folates, and cobalamins

  •  precluded these vitamins from playing any significant role in the rise of Hcy

plasma concentrations [27]. Analysis of plasma SAAs revealed

  • unmodified methioninemia, significantly 
  • elevated Hcy values (18.6 umol/L)
  • contrasting with significantly decreased plasma Cys and GSH values [27].

The significant lowering of classical

  • anthropometric parameters
    •  (body weight, BW;
    • body mass index, BMI)
  • together with that of the main plasma and urinary biomarkers of
    • metabolic (visceral) and
    • structural (muscular) compartments point to

an estimated 10 % shrinking of LBM [27].

Transthyretin (TTR)  and Lean Body Mass (LBM)

We have attached peculiar importance to the measurement of plasma transthyretin (TTR)

  1. this indicator integrates the evolutionary trends outlined by body protein reserves [35],
  2. providing from birth until death an overall and balanced estimate of LBM fluctuations [29].
  • In the absence of any superimposed inflammatory condition,
    • LBM and TTR profiles indeed reveal striking similarities [29].

Scientists belonging to the Foundation for Blood Research (Scarborough, Maine, 04074, USA) have recently published a large number of TTR results recorded
in 68,720 healthy US citizens aged 0-100 yr which constitute a comprehensive reference material to follow the shape of LBM fluctuations in relation with sex and age [29].

  • TTR concentrations plotted against Hcy values reveal a strongly negative correlation (r = –0.71)  [29,30], confirming that
      • the depletion of TBN and TBS stores plays a predominant role in the development of HHcy states.

The body of a reference man weighing 70 kg contains 64 M of N (1,800 g) and 4,400 mM of S (140 g) [36]. Our vegetarian subjects consume diets providing
low fat and high fiber content conferring a large spectrum of well described health benefits notably for the prevention of several chronic disorders such as
cancer and diabetes, together with an effective protection against the risk of hypercholesterolemia-induced CVD [37,38].
Plant-based regimens, however, do not supply appropriate amounts of

  • nitrogenous substrates of good biological value which are required to adequately fulfill mammalian tissue needs [30].
  • vegetable items contain suboptimal concentrations of both SAAs [33,34,39] below the customary RDA guidelines.

This dietary handicap may be further deteriorated by

  • unsuitable food processing [40] and by
  • the presence in plant products of naturally occurring anti-nutritional factors
    • such as tannins in cereal grains and
    • anti-trypsin or anti-chymotrypsin inhibitors in soybeans and kidney beans [41].

LBM loss

LBM shrinking may be the result of either

  • dysmaturation of body protein tissues as an effect of protracted dietary SAA deprivation
  • or of cytokine-induced depletion of body stores.

Although causally unrelated and evolving along dissimilar adaptive processes,

  • both physiopathologic entities lead to comparable LBM downsizing best
    • identified by declining plasma TTR ( measured alone or within combined formulas )
    • and subsequently rising Hcy values.

All parameters are downregulated with the sole exception of RM flux rates, indicating that

  • maintenance of Met homeostasis remains a high metabolic priority in protein-depleted states.

Stressful disorders are characterized by

  • overstimulation of all
  1. TM
  2. RM
  3. TS flux rates.

The severity and duration of initial impact determine the magnitude of protein tissue breakdown,

  • rendering an account of N : S urinary losses,
  • fluctuations of albuminuria and of
  • insulin resistance striving to contain LBM integrity.

Both physiopathologic entities are compromized in reducing the oxidative burden imposed by HHcy states owing to

  • defective synthesis and/or
  • enhanced overconsumption of Cys-GSH-H2S reducing molecules,
  • a condition still worsened by its co-existence with elemental S-deficiency.

IMPAIRMENT OF THE TRANSSULFURATION PATHWAY

The hypothesis that subclinical protein malnutrition might be involved in the occurrence of HHcy states via inhibition of cystathionine-b-synthase (CbS) activity
first arose in Senegal in 1986 [42] and was later corroborated in Central Africa [43]. The concept was clearly counterintuitive in that it was unexpected that

  • high Hcy plasma values might result from low intake of its precursor Met molecule.

Despite the low SAA intake of our vegetarian patients [27], plasma Met concentrations disclosed noticeable stability permitting

  • maintenance of the synthesis and functioning of myriads of Met dependent molecular, structural and metabolic compounds

These clinical investigations have received strong support from recent mouse [45] and rat [46] experiments submitted to Met-restricted regimens.
At the end of the Met-deprivation period, both animal species did manifest meaningful HHcy states (p<0.001) contrasting with

  • significantly lower BW (p<0.001) reduced by 33 % [45] and 44 % [46] of control, respectively.
  • the uniqueness of Met behavior stands in accordance with balance studies performed on large mammalian species showing
  • that the complete withdrawal of Met from otherwise normal diets causes the greatest rate of body loss,
    • nearly equal to that generated by protein-free regimens [47,48].

This efficient Met homeostatic mechanism is classically ascribed to a PLP-like inhibition of CbS activity exerted through

  • allosteric binding of S-adenosylmethionine (SAM) to the C-terminal regulatory domain of the enzyme [49,50].

The loss of CbS activity may develop via a (post)translational defect

  • independently from intrahepatic SAM concentrations [45].

We have postulated the existence of an independent sensor mechanism set in motion by TBS pool shrinkage and

  • reduced bioavailability of Met – its main building block – working as an inhibitory feedback loop of CbS activity [30].

Such Met-bodystat, likely to be centrally mediated, is to maintain unaltered Met disposal in conditions of

  • decreased dietary provision implies the fulfillment
  • of high metabolic priorities of survival value [30,44].

Whereas HHcy may be regarded as the dark side of a beneficial adaptive machinery [43],

  • impairment of the TS pathway also depresses the production of compounds situated downstream to the CbS blockade level,
  • notably Cys and GSH, keeping in mind that Cys may undergo reversible GSH conversion (Fig. 1).

The plasma concentration of both Cys and GSH reductants is indeed significantly decreased in our vegetarian subjects

  • by 33 % and 67 % of control, displaying negative correlations (r = –0.67 and –0.37, respectively) with HHcy values [27].

Reduced dietary intake of the preformed Cys molecule [27] and diminished Cys release from protein breakdown in malnourished states [51]

  • may contribute to the lowering effect.

The significantly decreased GSH blood levels may similarly be attributed to dietary composition since the tripeptide is mainly found in meat products

  • but is virtually absent from cereals, roots, milk and dairy items [52] and
  • because regimens lacking SAAs may lessen the production of blood GSH and its intrahepatic sequestration [53].

BIOGENESIS OF HYDROGEN SULFIDE

The TS degradation pathway schematically proceeds along two main PLP-dependent enzymatic reactions working in succession (Fig. 1).

  • The first is catalyzed by CbS (EC 4.2.1.22) governing the replacement of the hydroxyl group of serine with Hcy to generate Cysta plus H2O.
    • Cys may however substitute for serine and the replacement of its sulfhydryl group with Hcy releases Cysta and H2S instead of water [54].
  • The second is regulated by cystathionine-g-lyase (CgL, EC 4.4.1.1.) hydrolyzing Cysta to release Cys and alpha-ketobutyrate plus ammonia as side-products [55].
    •  Cys may also undergo nonoxidative desulfuration pathways leading to H2S or sulfanesulfur production [56] under the control of CbS or CgL enzymes.
    •  Cys may otherwise undergo oxidative conversion regulated by cysteine-dioxygenase (CDO, EC 1.13.11.20) which
      • catalyzes the replacement of the SH- group of Cys by SO3 – to yield cysteine-sulfinate [56].

This last compound may be further decarboxylated to hypotaurine that is finally oxidized to Tau (67 %) and SO4 2- oxyanions (33 %) [56]. CbS and CgL,  both cytosolic enzymes,

  • their relative contribution to the generation of H2S may vary according to
    • animal strains,
    • tissue specificities and
    • nutritional or physiopathological circumstances [23,24].

CbS and CgL are expressed in most organs such as liver, kidneys, brain, heart, large vessels, ileum and pancreas [57,58] potentially

  • subjected to HHcy-induced ROS injury while keeping the capacity to desulfurate Cys and to
  • locally produce H2S as cytoprotectant signaling agent.

CbS is the principal TS enzyme found in

  • cerebral glial cells and astrocytes [59].

CgL predominates in the

  • vascular system [60] whereas
      • both enzymes are present in the renal proximal tubules [61].

H2S is the third gaseous substrate found in the biosphere [18] after NO and CO. All three gases are characterized by

  • severe toxicity when inhaled at high concentrations.

In particular, H2S produced by anaerobic fermentation is

  • capable of causing respiratory death by
  • inhibition of mitochondrial cytochrome C oxidase [62].

NO, CO and H2S are synthesized from arginine, glycine and Cys, respectively, exerting at low concentrations major biological functions in living organisms.
Most of our knowledge on these atypical signal messengers [63] are derived from animal experiments and tissue cultures. These transmitter molecules may

  • share some properties in common such as penetration of cellular membranes independently from specific receptors [64].

They are also manifesting dissimilar activities: whereas NO and CO activate guanylyl cyclase to generate biological responses via cGMP-dependent kinases,

  • H2S induces Ca2+-dependent effects through ATP-sensitive K+ channels [65].

Some of these potentialities may work in concert while others operate antagonistically. For instance,

  • NO and H2S express vasorelaxant tone on endogenous smooth muscle [66]
  • but reveal different effects on large artery vessels [67].

These gaseous substances maintain whole body homeostasis through complex interactions and multifaceted crosstalks between signaling pathways.
Elemental S (32.064 as atomic mass) is a primordial constituent of lava flows in areas of volcanic or sedimental origin usually presenting as crown-shaped
stable octamolecules – hence its S8 symbolic denomination – which may conglomerate to form brimstone rocks. The vegetable kingdom is

  • unable to assimilate S8 and requires as prior step its natural or bacterial oxidation to SO4 2- derivatives before launching
  • the synthesis of SAA molecules along narrowly regulated metabolic pathways [30,44].

Distinct anabolic processes are identified in mammalian tissues which lack the enzymatic equipment required to organize sulfate oxyanions

  • but possess the capacity of direct S8 conversion into H2S.

S8 is poorly soluble in tap waters [68] may be taken up and transported to mammalian tissues loosely fastened to serum albumin (SA) [69].
S may also be covalently bound to intracellular S-atoms taking the form of sulfane-sulfur compounds [70] either

  • firmly attached to cytosolic organelles or in
  • untied form to mitochondria [57,58,71,72] to undergo
  • later release in response to specific endogenous requirements [71].

Sulfane-sulfur compounds are somewhat unstable and may decompose in the presence of reducing agents allowing the restitution of S [70,71].
S may either endorse the role of stimulatory factor of several mammalian apoenzyme activities as shown for

    • succinic dehydrogenase [73] and NADH dehydrogenase [74] or
  • operate as inhibitory agent of other mammalian apoenzymes such as
    • adenylate kinase [75] and liver tyrosine aminotransferase [76].

Elemental S resulting from dietary supply or from sulfane-sulfur decay may be subjected to

non-enzymatic reduction in the presence of Cys and GSH [25,26] and/or reducing equivalents obtained from

  • glucose oxidation [25], hence yielding at physiological pH additional provision of H2S.

The gaseous mediator is a weakly acidic molecule endowed with strong lipophilic affinities. In experimental models, the blockade of the TS cascade

  • at CbS or CgL levels significantly depresses or even
  • abolishes the vitally required production of Cys
  • operating at the crossroad of multiple converting processes (Fig. 1).

Addition of Cys to the incubation milieu

  • resumes the generation of H2S [19] in a Cys concentration-dependent manner [77].

The compounds situated downstream both cystathionases in the context of SAA deprivation

  • keep their functional potentialities
  • but are unable to express their converting Cys – H2S capacities
    • in the absence of precursor substrate.

Summing up

inhibition of CbS activity contributes to

  • promote efficient RM processes and
  • maintenance of Met homeostasis

but entails as side-effects

  1. upstream sequestration of Hcy molecules in biological fluids
  2. while decreasing the bioavailability of Cys and GSH
    • working as limiting factors for H2S production.

These last adverse effects thus constitute the Achilles heel of a remarkable adaptive machinery.

ROLES PLAYED BY HYDROGEN SULFIDE

The first demonstration that human tissues may reduce S to H2S was incidentally provided in 1924 when a man given colloid sulfur

  • for the treatment of polyarthritis did rapidly exhale the typical rotten egg malodor [78].
  • H2S may be produced by the intestinal flora [79] and serves as a metabolic fuel for colonocytes [80].
  • Prevention of endogenous poisoning by excessive enteral production is insured by the detoxifying activities of mucosal cells [81],
    • hindering any systemic effect of the gaseous substrate.

The normal H2S concentration measured in mammalian plasmas usually ranges from 10 to 100 μM with a mean average turning around 40-50 μM [19,21,82,83].
This H2S plasma level, appearing as the net product of organs possessing CbS and CgL enzymes and supplemented by the non-enzymatic conversion of S,

  • flows transiently into the vasculature and freely penetrates into all body cells.
  • Supposing that the gaseous reductant is evenly distributed in total body water (45 L in a 70 kg reference man) allows an estimate of
    • bioavailable H2S pool turning around 2 mM which represents, in terms of S participation, largely less than 1 / 1,000 of TBS.

The peculiar adaptive physiology of vegetarian subjects renders very unlikely that their TBS pool might be solicited to release

  • S-substrates prone to undergo conversion to nascent H2S molecules since
  •  they adapt to declining energy and nutrient intakes
  • by switching overall body economy toward downregulated steady state activities.

The release from TBS of substantial amounts of S-compounds occurs

  • only during the onset of hypercatabolic states as documented in trauma patients [31]
  • and in infectious diseases [84], exacting as preliminary step
  • cytokine-induced breakdown of tissue proteins, a selective hallmark of stressful disorders [85].

H2S in fulfilling ROS Scavenger Tasks

The limited disposal of H2S endogenously produced might be readily exhausted in fulfilling ROS scavenging tasks at the site of oxidative lesions.
All body organs generating H2S from TS enzymes are

  • simultaneously producers and consumers of the gaseous substrate whose actual concentration
  • reflects the balance between synthetic and catabolic rates [86].

Clinical investigations show that H2S concentrations found in cerebral homogenates from Alzheimer’s disease (AD) patients are

  • very much lower than expected from values measured in healthy brains [87], suggesting that
  • the gaseous messenger is locally submitted to enhanced consumption rates reflecting disease severity.

The concept is strongly supported by studies pointing to the

  • negative correlation linking the severity of AD to H2S plasma values [88].
  • in pediatric [89] and elderly [90] hypertensive patients as well
  • more severe HHcy-dependent oxidative burden is
    • associated with more intense H2S uptake rates.
  • These H2S cleansing properties are mainly exerted by mitochondrial organelles
    • known to be centrally involved in oxidative disorders [20,91].

Malnourished subjects deprived of Cys and GSH disposal thus incur the risk of H2S-deficiency

  • rendering them unable to properly overcome HHcy-imposed oxidative lesions.

The rapid exhaustion of H2S stores have detrimental consequences as shown disclosing

  • the beneficial effects of exogenous administration of commonly used sulfide salt donors (Na2S and NaHS)
  • generating H2S gas once in solution.

Such supply significantly augments

  • H2S plasma concentrations allowing to counteract ROS damages. 

H2S was primarily recognized as a physiological substrate working as

  • neuromodulator [92] and soon later as
  • vasorelaxant factor [65].

H2S is now regarded as endowed with a broader spectrum of biological properties [18],

  • operating as a general protective mediator
    • against most degenerative organ injuries,
  • being capable of neutralizing or
  • abolishing most ROS harmful effects.

Table 1 collects findings displaying that H2S may promote the synthesis and activity of several

  • anti-oxidative enzymes (catalases, Cu- and Mn-superoxide dismutases, GSH-peroxidases) and
  • stimulate the production of anti-inflammatory reactants (interleukin-10) or
  • conversely downregulate
    • pro-oxidative enzymes (collagenases, elastases),
    • pro-inflammatory cytokines (interleukine-1b, tumor-necrosis factor a) and
    • immune reactions (hyperleukocytosis, diapedesis, phagocytosis).

It has been calculated that 81.5% of H2S undergoes catabolic disintegration in the form of hydrosulfide anion (HS-) or sulfide anion (S2-) [117].
Since S is the main element in the diprotonated H2S molecule (34.08 as molecular mass), it may be considered that

  • partial or complete repair of HHcy-induced lesions constitutes the therapeutic proof that
  • S-deficiency is causally involved in the development of ROS damages.

The concept is sustained by the observation that all synthetic drugs (diclofenac, indomethacine, sildenafil) utilized as surrogate providers of H2S [64,118] are

  • characterized by a large diversity of molecular conformations but
  • share in common the presence of Satom(s) mimicking, once released,
  • H2S-like pharmacological properties.

It remains to be clarified whether the beneficial effects of S-fortification to S-deficient subjects are mediated, among other possible mechanisms, via

  • stimulation [73,74] of anti-oxidative enzymes or inhibition [75,76] of pro-oxidative enzymes.

It is only very recently that the essentiality of S has been recognized, causing Hcy elevation in deficient individuals [119]. It is worth reminding that the

  • gaseous NO substrate may work in concert or antagonistically [66,83] to fine-tuning the helpful properties exerted by H2S on body tissues.

Preliminary studies suggest for instance that NO operates, in combination with H2S, as a potential modulator of endothelial remodeling since

  •  NO-synthase isoforms contribute to the activation of  metalloproteinases involved in the regulation of the collagen/elastin balance defining vascular elastance [83,120].

SUBCLINICAL MALNUTRITION AS WORLDWIDE  SCOURGE

A growing body of data collected along the last decades indicates that

large proportions of mankind still suffer varying degrees of protein and energy deficiency that is associated with

  • increased morbidity and mortality rates.

The determinants of malnutrition are complex and interrelated, comprising

  • socioeconomic and political conditions,
  • insufficient dietary intakes,
  • inadequate caring practices and
  • superimposed inflammatory burden.

Children living in developing countries are paying a heavy toll to chronic malnutrition [121,122] whereas adult populations are handicapped by

  • feeble physical and working capacities,
  • increased vulnerability to infectious complications and
  • reduced life expectancy [123,124].

Cross-sectional studies collected in the eighties indicate that chronic malnutrition remains a worldwide scourge with

  • top prevalence recorded in Asia, whereas
  • sub-Saharan Africa endures medium nutritional distress and
  • Latin America appears as the least affected [125,126].

Along the last decades, significant progresses have been achieved in some countries such as Vietnam [127] and Bangladesh [128]

  • owing to appropriate education programs and improved economic development.

Inequalities however persist between middle class population groups mainly located in affluent urban areas and

  • underprivileged rural communities remaining stagnant on the sidelines of household income growth.

Representative models of these socio-economic disparities in global nutrition and health are illustrated in the two most populated countries in the world, China and India.
Large surveys undertaken in 105 counties of China and recently published have concluded that the rural communities haven’t yet reached the stage of overall welfare [129].
In India, similar investigations have documented that extreme poverty still prevails in the northern mountainous states of the subcontinent [130]. Taken together, southern
Asian countries fail to overcome malnutrition burden [131]. In some African countries, there exists even upward trends suggesting nutritional

deterioration over the years [132] still aggravated by a severe drought. The assessment of malnutrition in children usually rely on anthropometric criteria such as height-for-age, weight for-height, mid upper arm circumference and skinfold thickness allowing to draw the degree of stunting and wasting from these estimates. In adult subjects, BW and BMI are currently selected parameters to which some biochemical measurements are frequently added, notably SA, classical marker of protein nutritional status, and creatininuria (u-Cr), held as indicator of sarcopenia. The former biometric approaches are very useful in that they correctly provide a static picture of the declared stages of malnutrition but fail to recognize the dynamic mechanisms occurring during the preceding months and the adaptive alterations running behind.

Table 1. Reversal of HHcy-Induced Oxidative Damages by Administration of Exogenous H2S

BRAIN EFFECTS

H2S is overproduced in response to neuronal excitation [93], and

  1. increases the sensitivity of N-methyl-D-aspartate (NMDA) reactions to glutamate in hippocampal neurons [23,94].
  2.  improves long-term potentiation, a synaptic model of memory [92,93]
  3. stimulates the inhibitory effects of catalase and superoxide dismutase (SOD) in oxidative stress of endothelial cells [95].
  4.  regulates Ca 2+ homeostasis in microglial cells [96]and it inhibits TNFa expression in microglial cultures [97].
  5.  protects brain cells from neurotoxicity by preventing the rise of ROS in mitochondria [98].

CARDIOVASCULAR EFFECTS

  1. H2S releases vascular smooth muscle,
  2. inhibits platelet aggregation and
  3. reduces the force output of the left ventricule of the heart [18].
  4. maintains vascular smooth muscle tone [66] and
  5. insures protection against arterial hypertension [99].
  6. modifies leucocyte-vascular epithelium interactions in vivo  by
    1. modulating leucocyte adhesion and
    2. diapedesis at the site of inflammation [100].
  7. attenuates myocardial ischemia-reperfusion injury by
    1. depressing IL-1b and mitochondrial function [20].
  8. upregulates the expression of depressed anti-oxidative enzymes in heart infarction and
    1. inhibits myocardial injury [21].
  9. alleviates smooth muscle pain by
    1. stimulating K+ ATP channels [101].
  10. prevents apoptosis of human neutrophil cells
    1. by inhibiting p38 MAP kinase and caspase 3 [102].
  11. potentiates angiogenesis and wound healing [103].

RENAL EFFECTS

  1. H2S downregulates the increased activity of metalloproteinases 2 and 9 involved in extracellular matrix degradation (elastases, collagenases) [19].
  2. Prevents apoptotic cell death in renal cortical tissues [19].
  3. Improves the expression of desmin (marker of podocyte injury) and
  4. restores the drop of nephrin (component of normal slit diaphragm) in the cortical tissues
    1. resulting in reduced proteinuria [19].
  5. Induces hypometabolism revealing protective effects on renal function and survival [104].
  6. Normalizes GSH status and production of ROS in renal diseases [19].
  7. Controls renal ischemia-reperfusion injury and dysfunction [105].
  8. Depresses the expression of inflammatory molecules involved in glomerulosclerosis [106].
  9. Increases renal blood flow, glomerular filtration and urinary Na+ excretion [77].

OTHER ORGAN EFFECTS
Gastrointestinal

  1. H2S insures protection against ROS stress in gastric mucosal epithelia [22].
  2. Accelerates gastric ulcer healing [107].
  3. Reduces gastric injury caused by nonsteroidal anti-inflammatory drugs [108].
  4. Relaxes ileal smooth muscle tone and increases colonic secretions [79].
  5. Attenuates intestinal ischemia-reperfusion injury by increasing SOD and GSH peroxidase status [109].
  6. Stimulates insulin secretion [110] and controls inflammatory events associated with acute pancreatitis [111].
  7. Alleviates hepatic ischemia-reperfusion injury [112].

Pulmonary

  1. Prevents lung oxidative stress in hypoxic pulmonary hypertension caused by low GSH content [113].
  2. Promotes SOD and catalase activities and reduces the production of malondialdehyde in oxidative lung injury [114].
  3. Reduces lung inflammation and remodeling in asthmatic animals [115] and in pulmonary hypertension [116].  ..(see OCCJ 2011;4:34-44)

Assessing Protein-Depleted States

  1.  SA is an insensitive marker of protein-depleted states compared to TTR [134]
  2. SA is an indicator of population than of individual protein status in subclinical PEM.
  3. u-Cr is likewise a meagerly informative tool as 10 % loss of muscle mass is required before it reaches significantly decreased urinary concentrations [135].

The data imply that the magnitude of subclinical malnutrition is largely

  • underscored when classical biometric and laboratory investigations are performed.

Moreover, ruling out the protein component involved in HHcy epidemiology and confining solely attention to the B-vitamin triad led to unachieved conclusions.

  • surveys undertaken in Taiwan [136] and in India [137] established HHcy variance turning around 30 %, indicating that
  • a sizeable percentage of subjects do not come within the vitamin shortage concept.
  • only one recent review recommending the use of TTR in vegetarian subjects [138].

The main reason for making the choice of TTR is grounded on the striking similar plasma profile disclosed by this marker with both LBM and Hcy [29].
Under healthy conditions, the 3 parameters –

  • TTR,
  • LBM,
  • Hcy –
    • indeed show low  concentrations at birth,
    • linear increase without sexual difference in preadolescent children,
    • gender dimorphism in teenagers with higher values recorded in adolescent male subjects
    • thereafter maintenance of distinct plateau levels during adulthood [29,139,140].

Under morbid circumstances, the plasma concentrations of

  • Hcy manifest gradual elevation
  • negatively correlated with LBM downsizing and
  • TTR decline.

In vegetarian subjects and subclinically malnourished patients,

  • rising Hcy and
  • diminished TTR plasma concentrations look as mirror image of each other,
    • revealing divergent distortion from normal and
    • allowing early detection of preclinical steps
    • at the very same time both SA and u-Cr markers still remain silent.

Any disease process characterized by quantitative or qualitative dietary protein restriction or intestinal malabsorption

  • may cause LBM shrinking,
  • downregulation of TTR concentrations and
  • subsequent HHcy upsurge.

These conditions are documented in frank kwashiorkor [141], subclinical protein restriction [27,43] and anorexia nervosa [142].
In patients submitted to weight-reducing programs,

  • LBM was found the sole independent variable
  • negatively correlated with rising Hcy values [143].

Morbid obesity may be alleviated by medical treatment [143] or surgical gastroplasty [144,145],

  • conditions frequently associated with secondary malabsorptive syndromes and malnutrition [146],

How does this account play out in the typical patient with excessive body fat, lipoprotein disoreder, and perhaps diabetes and disordered sleep – an account of acquired HHcy?
Have the studies been done?  Would you expect to see a clear benefit from reduced HHcy_emia  based on a 30 min daily walk, and

  • eating of well fat trimmed meats, fruits and vegetables, and fish, flax seed, or krill oil?

In westernized countries, subclinical protein-depleted states are illustrated in immigrants originating from

  • developing regions but keeping alive their traditional feeding practices [147] or
  • by communities having adopted, for socio-cultural reasons, strict vegan dietary lifestyles [148].

THE ADDITIONAL BURDEN OF S-DEFICIENCY

After N, K and P, elemental S is recognized as the fourth most important macronutrient required for plant development. The essentiality of S in the vegetable kingdom
arose from observations made many decades ago by pedologists and agronomists [149,150] revealing that the withdrawal of sulfate salts from nutrient sources produces
rapid growth retardation,

  • depressed chlorophyllous synthesis,
  • yellowing of leaves and
  • reduction in fertility and crop yields.

A large number of field studies, mainly initiated for economical reasons, has provided continuing gain in fundamental and applied knowledge and led to the overall consensus

  • that SO4 2- -deficiency is a major wordwide problem [151,152].

Field investigations have shown that the concentration of SO4 2- oxyanions in soils and drinking waters

  • may reveal considerable variations ranging from less than 2 mg/L to more than 1 g/L,
  • meaning a ratio exceeding 1 / 500 under extreme circumstances [30].

The main causal factors responsible for unequal distribution of SO4 2- oxyanions are geographical distance from eruptive sites and

  • intensity of soil weathering in rainy countries.

SO4 2- -dependent nutritional deficiencies entail detrimental effects to most African and Latin American crops [151]

  • reaching nevertheless top incidence in southeastern Asia [151,153].
  • and the Indo-Gangetic plain extending from Pakistan to Bangladesh and covering the North of India and Nepal [154].
  1. Intensive agricultural production,
  2. lack of animal manure and
  3. use of fertilizers providing N, K and P substrates
  4. but devoid of sulfate salts may further aggravate that imbalanced situation.

As global population increases steadily and the production of staple plants predicted to escalate considerably,

  • SO4 2- deficient disorders are expected to become more pregnant along the coming years [155] with significant harmful impact for mankind.

Nevertheless, effective preventive efforts are developed in some countries aiming at fortification of soils mainly

  • by ammonium sulfate or calcium sulfate (gypsum) salts,
  • resulting in meaningful improvements in crop yield,
  • SAAs content and biological value and
  • opening more optimistic perspectives for livestock and human consumption [152,155-158].

Contrasting with the tremendously high amounts of data accumulated over decades by pedologists and agronomists on sulfate requirements and metabolism,
the available knowledge on elemental sulfur in human nutrition looks like a black hole. Despite the fact that S8 follows H, C, O, N, Ca and P as the seven most
abundant element in mammalian tissues, it appears as a forgotten item. Not the slightest attention is dedicated to S8 in the authoritative “Present Knowledge
in Nutrition” series of monographs even though they go over most oligo- and trace-elements in minute detail.

The geographical distribution of S8 throughout the earth’s crust is not well-known

  • as extreme paucity of measurements in soils and tap waters prevents reaching a comprehensive overview.

Nevertheless, and because S8 is the obligatory precursor substrate for the oxidative production of sulfate salts,

a decremental dispersion pattern paralleling those of SO4 2- oxyanions is likely to occur with

  • highest values recorded in the vicinity of volcano sources
  •  and lowest values found in remote and washed-out areas.

Obviously, a great deal of research on elemental S remains to be completed by clinical biochemists before rejoining the status of plant agronomy.
Taken together, these data imply that subclinically malnourished subjects living in areas recognized as

  • SO4 2- -deficient for the vegetable kingdom also
  • incur increased risks to become S8-depleted.

This clinical entity most probably prevails in all regions, notably Northern India, where protein malnutrition [130] and sulfur-deficiency [154] coexist.
Combination of both nutritional deprivations explains why the bulk of local dwellers, including young subjects [159,160], may develop HHcy states and CVD disorders

  • characterized by strong refractoriness to vitamin-B supplementation [160] or
  • high incidence of stroke [161] unrelated to the classical Framingham criteria.

The current consensus is that “the problem of CVD in South Asia is different in etiology and magnitude from other parts of the world” [162]. These disquieting findings are
confirmed in several Asian countries [163] and have prompted local cardiologists to exhort their governments to focus more attention on CVD epidemiology [164].

CONCLUDING REMARKS

  1.  vegetarian subjects are not protected against the risk of CVD and stroke which should no longer be regarded as solely affecting populations living in westernized societies
  • whose morbidity and mortality risks are stratified by classical Framingham criteria.
  • Likewise hypercholesterolemia, hyperhomocysteinemia should be incriminated as
    • emblematic risk factor for a panoply of CVD and related disorders.
  • Whereas the causality of cholesterol and lipid fractions largely prevails in affluent societies consuming high amounts of animal-based items,
    • that of homocysteine predominates in population groups whose dietary lifestyle gives more importance to plant products.

 MAIN PHYSICO-CHEMICAL AND METABOLIC CHARACTERISTICS* OF 3 CARRIER-PROTEINS INVOLVED IN THE STRESS RESPONSE

CBG

TTR

RBP

Molecular mass (Da.)

42,650

54,980

21,200

Conformation

monomeric

tetrameric

monomeric

Amino acid sequence

383

4 x 127

182

Carbohydrate load

18 % glycosylated

unglycosylated

unglycosylated

Hormonal binding sites

one for cortisol

two for TH

one for retinol

Association constant (M-1)

3 x 107

7 x 107 (T4)

1.9 x 107

Normal plasma concentration

30 mg/L.

300 mg/L.

50 mg/L.

Biological half-life

5 days

2 days

14 hrs

Bound ligand  concentration

120 µg/L.

80 µg TT4/L.

500 µg/L.

Free ligand concentration

5 µg/L.

20 ng FT4/L.

1 µg/L.

Ratio free : bound ligands

4 %

0.034 %

0.14 %

Distribution volume of free moieties

18 L.

12 L.

18 L.

STIMULATORY AND INHIBITORY EFFECTS MODULATED

BY GLUCOCORTICOIDS

TARGET SYSTEMS

 

INDUCED EFFECTS

REF.

Thymidine kinase

_

transcription of induced DNA into RNA

112

Alkaline phosphodiesterase I

_

cleavage of phosphodiester bonds

113

Tyrosine transaminase

_

transfer of tyrosine amino group

114

Tryptophane oxygenase

_

formylkynurenine and Trp catabolites

115

Alkaline phosphatase

_

release of P from phosphoric esters

116

Phosphoenolpyruvate carboxykinase (liver)

_

glycolysis from pyruvate and ATP production

117

Mannolsyltransferases

_

dolichol-linked glycosylation of APRs

118

Haptoglobin

_

APR combining with hemoglobin

119

α1-Anti (chymo) trypsin (α1 AT, α1 ACT)

_

serpin molecules allowing N-sparing effects

120

α1-Acid glycoprotein (AGP)

_

glycosylated APR with antibody-like actions

121

Serum amyloid protein (SAA)

_

defense systems against oxidative burst

122

γ-Fibrinogen

_

clotting processes and tissue repair

123

C-Reactive Protein (CRP)

_

complement processes and opsonization

124

Corticosteroid-binding globulin (CBG)

_

CBG levels, favoring free hypercortisolemia

100

Phosphoenolpyruvate carboxykinase (adipocytes)

_

ATP turnover and glycolysis

113

THE DUAL MORBID ENTITIES CAUSING LBM DOWNSIZING AND SUBSEQUENT Hcy UPSURGE 

Primary causal factor

  1. Reduced dietary intake of methionine (39,151,152)
  2. Cytokine-induced tissue breakdown (164,165)

Main clinical conditions

  1. Protein malnutrition,
  2. veganism,
  3. intestinal malabsorption (139,155,156,158-160,281)
  4. Trauma,
  5. sepsis,
  6. burns,
  7. Inflammatory & neoplastic disorders (163,166,170,176,179,180)

Physiopathologic mechanisms

  1. Unachieved LBM replenishment (30,33)
  2. Excessive LBM losses (33,167,179)

Overall protein metabolic status

  1. Downregulated
  2. Upregulated

Plasma biomarker(s) of protein status

  1. Transthyretin (TTR) (144,145)
  2. TTR coupled with CRP or other inflammatory indices (31,177,178,284,285)

Insulin resistance status

  1. Normal or low (286)
  2. Increased in proportion of tissue breakdown (177,178,181-183)

status of Cys-GSH-H2S reducing molecules

  1. Decreased enzymatic and non-enzymatic production (39,161,162,287)
  2. Increased production cancelled out by tissue overconsumption (78,171)

Urinary SO42- and S-compounds

  1. Decreased kidney output (76,78,79)
  2. Variable depending on exogenous SAA supply and
  • extent of tissue breakdown (78,163,168,173)

Transmethylation pathway

  1. Depressed (48,93)
  2. Overstimulated (169)

Remethylation pathway

  1. Stimulated (76,83,153)
  2. Overstimulated (169)

Transsulfuration pathway

  1. Inhibited (49,76,83)
  2. Overstimulated (170,173)


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Received: September 30, 2011 Revised: October 12, 2011 Accepted: October 12, 2011
© Yves Ingenbleek; Licensee Bentham Open.
This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

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English: Biosynthesis of cysteine from homocysteine and serine via cystathione intermediate (Photo credit: Wikipedia)

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Expanding the Genetic Alphabet and Linking the Genome to the Metabolome


English: The citric acid cycle, also known as ...

English: The citric acid cycle, also known as the tricarboxylic acid cycle (TCA cycle) or the Krebs cycle. Produced at WikiPathways. (Photo credit: Wikipedia)

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

 

Reporter& Curator:  Larry Bernstein, MD, FCAP

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Unlocking the diversity of genomic expression within tumorigenesis and “tailoring” of therapeutic options

1. Reshaping the DNA landscape between diseases and within diseases by the linking of DNA to treatments

In the NEW York Times of 9/24,2012 Gina Kolata reports on four types of breast cancer and the reshaping of breast cancer DNA treatment based on the findings of the genetically distinct types, which each have common “cluster” features that are driving many cancers.  The discoveries were published online in the journal Nature on Sunday (9/23).  The study is considered the first comprehensive genetic analysis of breast cancer and called a roadmap to future breast cancer treatments.  I consider that if this is a landmark study in cancer genomics leading to personalized drug management of patients, it is also a fitting of the treatment to measurable “combinatorial feature sets” that tie into population biodiversity with respect to known conditions.   The researchers caution that it will take years to establish transformative treatments, and this is clearly because in the genetic types, there are subsets that have a bearing on treatment “tailoring”.   In addition, there is growing evidence that the Watson-Crick model of the gene is itself being modified by an expansion of the alphabet used to construct the DNA library, which itself will open opportunities to explain some of what has been considered junk DNA, and which may carry essential information with respect to metabolic pathways and pathway regulation.  The breast cancer study is tied to the  “Cancer Genome Atlas” Project, already reported.  It is expected that this work will tie into building maps of genetic changes in common cancers, such as, breast, colon, and lung.  What is not explicit I presume is a closely related concept, that the translational challenge is closely related to the suppression of key proteomic processes tied into manipulating the metabolome.

Saha S. Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations. 9/12/2012. PharmaceuticalIntelligence.Wordpress.com

Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature  Sept 14-20, 2012

Sarkar A. Prediction of Nucleosome Positioning and Occupancy Using a Statistical Mechanics Model. 9/12/2012. PharmaceuticalIntelligence.WordPress.com

Heijden et al.   Connecting nucleosome positions with free energy landscapes. (Proc Natl Acad Sci U S A. 2012, Aug 20 [Epub ahead of print]).  http://www.ncbi.nlm.nih.gov/pubmed/22908247

2. Fiddling with an expanded genetic alphabet – greater flexibility in design of treatment (pharmaneogenesis?)

Diagram of DNA polymerase extending a DNA stra...

Diagram of DNA polymerase extending a DNA strand and proof-reading. (Photo credit: Wikipedia)

A clear indication of this emerging remodeling of the genetic alphabet is a new
study led by scientists at The Scripps Research Institute appeared in the
June 3, 2012 issue of Nature Chemical Biology that indicates the genetic code as
we know it may be expanded to include synthetic and unnatural sequence pairing (Study Suggests Expanding the Genetic Alphabet May Be Easier than Previously Thought, Genome). They infer that the genetic instructions for living organisms
that is composed of four bases (C, G, A and T)— is open to unnatural letters. An expanded “DNA alphabet” could carry more information than natural DNA, potentially coding for a much wider range of molecules and enabling a variety of powerful applications. The implications of the application of this would further expand the translation of portions of DNA to new transciptional proteins that are heretofore unknown, but have metabolic relavence and therapeutic potential. The existence of such pairing in nature has been studied in Eukariotes for at least a decade, and may have a role in biodiversity. The investigators show how a previously identified pair of artificial DNA bases can go through the DNA replication process almost as efficiently as the four natural bases.  This could as well be translated into human diversity, and human diseases.

The Romesberg laboratory collaborated on the new study and his lab have been trying to find a way to extend the DNA alphabet since the late 1990s. In 2008, they developed the efficiently replicating bases NaM and 5SICS, which come together as a complementary base pair within the DNA helix, much as, in normal DNA, the base adenine (A) pairs with thymine (T), and cytosine (C) pairs with guanine (G). It had been clear that their chemical structures lack the ability to form the hydrogen bonds that join natural base pairs in DNA. Such bonds had been thought to be an absolute requirement for successful DNA replication, but that is not the case because other bonds can be in play.

The data strongly suggested that NaM and 5SICS do not even approximate the edge-to-edge geometry of natural base pairs—termed the Watson-Crick geometry, after the co-discoverers of the DNA double-helix. Instead, they join in a looser, overlapping, “intercalated” fashion that resembles a ‘mispair.’ In test after test, the NaM-5SICS pair was efficiently replicable even though it appeared that the DNA polymerase didn’t recognize it. Their structural data showed that the NaM-5SICS pair maintain an abnormal, intercalated structure within double-helix DNA—but remarkably adopt the normal, edge-to-edge, “Watson-Crick” positioning when gripped by the polymerase during the crucial moments of DNA replication. NaM and 5SICS, lacking hydrogen bonds, are held together in the DNA double-helix by “hydrophobic” forces, which cause certain molecular structures (like those found in oil) to be repelled by water molecules, and thus to cling together in a watery medium.

The finding suggests that NaM-5SICS and potentially other, hydrophobically bound base pairs could be used to extend the DNA alphabet and that Evolution’s choice of the existing four-letter DNA alphabet—on this planet—may have been developed allowing for life based on other genetic systems.

3.  Studies that consider a DNA triplet model that includes one or more NATURAL nucleosides and looks closely allied to the formation of the disulfide bond and oxidation reduction reaction.

This independent work is being conducted based on a similar concep. John Berger, founder of Triplex DNA has commented on this. He emphasizes Sulfur as the most important element for understanding evolution of metabolic pathways in the human transcriptome. It is a combination of sulfur 34 and sulphur 32 ATMU. S34 is element 16 + flourine, while S32 is element 16 + phosphorous. The cysteine-cystine bond is the bridge and controller between inorganic chemistry (flourine) and organic chemistry (phosphorous). He uses a dual spelling, using  sulfphur to combine the two referring to the master catalyst of oxidation-reduction reactions. Various isotopic alleles (please note the duality principle which is natures most important pattern). Sulfphur is Methionine, S adenosylmethionine, cysteine, cystine, taurine, gluthionine, acetyl Coenzyme A, Biotin, Linoic acid, H2S, H2SO4, HSO3-, cytochromes, thioredoxin, ferredoxins, purple sulfphur anerobic bacteria prokaroytes, hydrocarbons, green sulfphur bacteria, garlic, penicillin and many antibiotics; hundreds of CSN drugs for parasites and fungi antagonists. These are but a few names which come to mind. It is at the heart of the Krebs cycle of oxidative phosphorylation, i.e. ATP. It is also a second pathway to purine metabolism and nucleic acids. It literally is the key enzymes between RNA and DNA, ie, SH thiol bond oxidized to SS (dna) cysteine through thioredoxins, ferredoxins, and nitrogenase. The immune system is founded upon sulfphur compounds and processes. Photosynthesis Fe4S4 to Fe2S3 absorbs the entire electromagnetic spectrum which is filtered by the Allen belt some 75 miles above earth. Look up chromatium vinosum or allochromatium species.  There is reasonable evidence it is the first symbiotic species of sulfphur anerobic bacteria (Fe4S4) with high potential mvolts which drives photosynthesis while making glucose with H2S.
He envisions a sulfphur control map to automate human metabolism with exact timing sequences, at specific three dimensional coordinates on Bravais crystalline lattices. He proposes adding the inosine-xanthosine family to the current 5 nucleotide genetic code. Finally, he adds, the expanded genetic code is populated with “synthetic nucleosides and nucleotides” with all kinds of customized functional side groups, which often reshape nature’s allosteric and physiochemical properties. The inosine family is nature’s natural evolutionary partner with the adenosine and guanosine families in purine synthesis de novo, salvage, and catabolic degradation. Inosine has three major enzymes (IMPDH1,2&3 for purine ring closure, HPGRT for purine salvage, and xanthine oxidase and xanthine dehydrogenase.

English: DNA replication or DNA synthesis is t...

English: DNA replication or DNA synthesis is the process of copying a double-stranded DNA molecule. This process is paramount to all life as we know it. (Photo credit: Wikipedia)

3. Nutritional regulation of gene expression,  an essential role of sulfur, and metabolic control 

Finally, the research carried out for decades by Yves Ingenbleek and the late Vernon Young warrants mention. According to their work, sulfur is again tagged as essential for health. Sulfur (S) is the seventh most abundant element measurable in human tissues and its provision is mainly insured by the intake of methionine (Met) found in plant and animal proteins. Met is endowed with unique functional properties as it controls the ribosomal initiation of protein syntheses, governs a myriad of major metabolic and catalytic activities and may be subjected to reversible redox processes contributing to safeguard protein integrity.

Consuming diets with inadequate amounts of methionine (Met) are characterized by overt or subclinical protein malnutrition, and it has serious morbid consequences. The result is reduction in size of their lean body mass (LBM), best identified by the serial measurement of plasma transthyretin (TTR), which is seen with unachieved replenishment (chronic malnutrition, strict veganism) or excessive losses (trauma, burns, inflammatory diseases).  This status is accompanied by a rise in homocysteine, and a concomitant fall in methionine.  The ratio of S to N is quite invariant, but dependent on source.  The S:N ratio is typical 1:20 for plant sources and 1:14.5 for animal protein sources.  The key enzyme involved with the control of Met in man is the enzyme cystathionine-b-synthase, which declines with inadequate dietary provision of S, and the loss is not compensated by cobalamine for CH3- transfer.

As a result of the disordered metabolic state from inadequate sulfur intake (the S:N ratio is lower in plants than in animals), the transsulfuration pathway is depressed at cystathionine-β-synthase (CβS) level triggering the upstream sequestration of homocysteine (Hcy) in biological fluids and promoting its conversion to Met. They both stimulate comparable remethylation reactions from homocysteine (Hcy), indicating that Met homeostasis benefits from high metabolic priority. Maintenance of beneficial Met homeostasis is counterpoised by the drop of cysteine (Cys) and glutathione (GSH) values downstream to CβS causing reducing molecules implicated in the regulation of the 3 desulfuration pathways

4. The effect on accretion of LBM of protein malnutrition and/or the inflammatory state: in closer focus

Hepatic synthesis is influenced by nutritional and inflammatory circumstances working concomitantly and liver production of  TTR integrates the dietary and stressful components of any disease spectrum. Thus we have a depletion of visceral transport proteins made by the liver and fat-free weight loss secondary to protein catabolism. This is most accurately reflected by TTR, which is a rapid turnover protein, but it is involved in transport and is essential for thyroid function (thyroxine-binding prealbumin) and tied to retinol-binding protein. Furthermore, protein accretion is dependent on a sulfonation reaction with 2 ATP.  Consequently, Kwashiorkor is associated with thyroid goiter, as the pituitary-thyroid axis is a major sulfonation target. With this in mind, it is not surprising why TTR is the sole plasma protein whose evolutionary patterns closely follow the shape outlined by LBM fluctuations. Serial measurement of TTR therefore provides unequaled information on the alterations affecting overall protein nutritional status. Recent advances in TTR physiopathology emphasize the detecting power and preventive role played by the protein in hyper-homocysteinemic states.

Individuals submitted to N-restricted regimens are basically able to maintain N homeostasis until very late in the starvation processes. But the N balance study only provides an overall estimate of N gains and losses but fails to identify the tissue sites and specific interorgan fluxes involved. Using vastly improved methods the LBM has been measured in its components. The LBM of the reference man contains 98% of total body potassium (TBK) and the bulk of total body sulfur (TBS). TBK and TBS reach equal intracellular amounts (140 g each) and share distribution patterns (half in SM and half in the rest of cell mass). The body content of K and S largely exceeds that of magnesium (19 g), iron (4.2 g) and zinc (2.3 g).

TBN and TBK are highly correlated in healthy subjects and both parameters manifest an age-dependent curvilinear decline with an accelerated decrease after 65 years. Sulfur Methylation (SM) undergoes a 15% reduction in size per decade, an involutive process. The trend toward sarcopenia is more marked and rapid in elderly men than in elderly women decreasing strength and functional capacity. The downward SM slope may be somewhat prevented by physical training or accelerated by supranormal cytokine status as reported in apparently healthy aged persons suffering low-grade inflammation or in critically ill patients whose muscle mass undergoes proteolysis.

5.  The results of the events described are:

  • Declining generation of hydrogen sulfide (H2S) from enzymatic sources and in the non-enzymatic reduction of elemental S to H2S.
  • The biogenesis of H2S via non-enzymatic reduction is further inhibited in areas where earth’s crust is depleted in elemental sulfur (S8) and sulfate oxyanions.
  • Elemental S operates as co-factor of several (apo)enzymes critically involved in the control of oxidative processes.

Combination of protein and sulfur dietary deficiencies constitute a novel clinical entity threatening plant-eating population groups. They have a defective production of Cys, GSH and H2S reductants, explaining persistence of an oxidative burden.

6. The clinical entity increases the risk of developing:

  • cardiovascular diseases (CVD) and
  • stroke

in plant-eating populations regardless of Framingham criteria and vitamin-B status.
Met molecules supplied by dietary proteins are submitted to transmethylation processes resulting in the release of Hcy which:

  • either undergoes Hcy — Met RM pathways or
  • is committed to transsulfuration decay.

Impairment of CβS activity, as described in protein malnutrition, entails supranormal accumulation of Hcy in body fluids, stimulation of activity and maintenance of Met homeostasis. The data show that combined protein- and S-deficiencies work in concert to deplete Cys, GSH and H2S from their body reserves, hence impeding these reducing molecules to properly face the oxidative stress imposed by hyperhomocysteinemia.

Although unrecognized up to now, the nutritional disorder is one of the commonest worldwide, reaching top prevalence in populated regions of Southeastern Asia. Increased risk of hyperhomocysteinemia and oxidative stress may also affect individuals suffering from intestinal malabsorption or westernized communities having adopted vegan dietary lifestyles.

Ingenbleek Y. Hyperhomocysteinemia is a biomarker of sulfur-deficiency in human morbidities. Open Clin. Chem. J. 2009 ; 2 : 49-60.

7. The dysfunctional metabolism in transitional cell transformation

A third development is also important and possibly related. The transition a cell goes through in becoming cancerous tends to be driven by changes to the cell’s DNA. But that is not the whole story. Large-scale techniques to the study of metabolic processes going on in cancer cells is being carried out at Oxford, UK in collaboration with Japanese workers. This thread will extend our insight into the metabolome. Otto Warburg, the pioneer in respiration studies, pointed out in the early 1900s that most cancer cells get the energy they need predominantly through a high utilization of glucose with lower respiration (the metabolic process that breaks down glucose to release energy). It helps the cancer cells deal with the low oxygen levels that tend to be present in a tumor. The tissue reverts to a metabolic profile of anaerobiosis.  Studies of the genetic basis of cancer and dysfunctional metabolism in cancer cells are complementary. Tomoyoshi Soga’s large lab in Japan has been at the forefront of developing the technology for metabolomics research over the past couple of decades (metabolomics being the ugly-sounding term used to describe research that studies all metabolic processes at once, like genomics is the study of the entire genome).

Their results have led to the idea that some metabolic compounds, or metabolites, when they accumulate in cells, can cause changes to metabolic processes and set cells off on a path towards cancer. The collaborators have published a perspective article in the journal Frontiers in Molecular and Cellular Oncology that proposes fumarate as such an ‘oncometabolite’. Fumarate is a standard compound involved in cellular metabolism. The researchers summarize that shows how accumulation of fumarate when an enzyme goes wrong affects various biological pathways in the cell. It shifts the balance of metabolic processes and disrupts the cell in ways that could favor development of cancer.  This is of particular interest because “fumarate” is the intermediate in the TCA cycle that is converted to malate.

Animation of the structure of a section of DNA...

Animation of the structure of a section of DNA. The bases lie horizontally between the two spiraling strands. (Photo credit: Wikipedia)

The Keio group is able to label glucose or glutamine, basic biological sources of fuel for cells, and track the pathways cells use to burn up the fuel.  As these studies proceed, they could profile the metabolites in a cohort of tumor samples and matched normal tissue. This would produce a dataset of the concentrations of hundreds of different metabolites in each group. Statistical approaches could suggest which metabolic pathways were abnormal. These would then be the subject of experiments targeting the pathways to confirm the relationship between changed metabolism and uncontrolled growth of the cancer cells.

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