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Posts Tagged ‘active compounds’


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The majority of living forms depend for their functioning upon two classes of biocatalysts, the enzymes and the hormones. These biocatalysts permit the diverse chemical reactions of the organism to proceed at 38°C with specificity and at rates frequently unattainable in vitro at elevated temperatures with similar reactants. The physiologic importance of enzymes and hormones is evident not only under normal circumstances, but is reflected clinically in the diverse descriptions of errors of metabolism, due to lack or deficiency of one or more enzymes, and the numerous hypo and hyper functioning states resulting from imbalance of hormonal supply.

 

In as much as both enzymes and hormones function, with rare exception, to accelerate the rates of processes in cells, investigators have sought possible interrelationships and interactions of enzymes and hormones, particularly as a basis for the mechanism of hormonal action. It has seemed logical to hypothesize that hormones, while not essential for reactions to proceed but never the less affecting the rates of reactions, may function by altering either the concentration or activity of the prime cellular catalysts, the enzymes. This proposed influence of hormones on enzymatic activity might be a primary, direct effect achieved by the hormone participating as an integral part of an enzyme system, or an indirect influence based upon the hormone altering the concentration of available enzyme and/or substrate utilized by a particular enzyme. Many publications have described alterations in the activity of enzymes in various tissues following administration in vivo of diverse hormonal preparations. However, it is not possible to judge, in the in vivo experiments, whether the reported effects are examples of direct enzyme-hormone interaction, or an indirect influence of the hormone mediated via one or more metabolic pathways, and therefore other enzyme systems whose activities are not being measured. Data from in-vivo studies of this type are thus not pertinent to a discussion of direct hormone-enzyme interaction.

 

Enzyme hormone interaction, as seen, for example, in the profound role of the enzymes of the liver in the metabolism of certain hormones, is of paramount importance in determining the effectiveness of these hormones. The ability of the organic chemist to prepare synthetic hormonal derivatives which are relatively resistant to enzymatic processes in the liver has been of outstanding value for approaches to oral hormonal therapy. Largely unexplored as yet is the possibility that enzyme-hormone interactions may lead to the production of physiologically more active substances from compounds normally synthesized and secreted by a particular endocrine gland. It may be said at the outset that in no instance has a hormone been demonstrated to influence the rate of a cellular reaction by functioning as a component of an enzyme system.

 

It is plausible that enzymes in a pathway might be structurally conserved because of their similar substrates and products for linked metabolic steps. However, this is not typically observed, and sequence analysis confirms the lack of convergent or divergent evolution. One might postulate that, if the folds or overall structures of the enzymes in a pathway are not conserved, then perhaps at least pathway-related active site similarities would exist. It is true that metal-binding sites and nucleotide-binding sites are structurally conserved. For example, cofactor-binding motifs for zinc, ATP, biopterin and NAD have been observed and biochemically similar reactions appear to maintain more structural similarity than pathway-related structural motifs. In general, ‘horizontal’ structural equivalency is prevalent in that chemistry-related structural similarities exist, but ‘vertical’ pathway-related structural similarities do not hold.

 

For metabolic pathways, protein fold comparisons and corresponding active site comparisons are sometimes possible if structural and functional homology exists. Unfortunately, with the current structural information available, the majority of active sites that can be structurally characterized are not similar within a metabolic pathway. Other examples exist of nearly completed pathways, for example, the tricarboxylic acid (TCA) cycle, and similar observations are observed. Situations in which different metals are incorporated in enzyme active sites lead to inherently different catalytic portions of the active sites. Slight differences in the ligand-binding portions of the respective active sites must lead to the observed differences in pathway-related enzyme specificities. These modifications in enzymatic activity are similar to what Koshland and co-workers previously observed. They showed that very minor active site perturbations to isocitrate dehydrogenase had drastic effects on catalysis.

 

Molecular level understanding of chemical and biological processes requires mechanistic details and active site information. The current knowledge regarding enzyme active sites is incomplete. Even in situations in which ATP-, ADP- or NAD(P)+-binding domains are observed or in situations in which similar folds are found (e.g. even for related kinases or for proteins involved in the immune system), structural comparisons do not yield specific details about active sites and it is not possible to predict where the substrate binds or to identify determinants of active site substrate specificity. Therefore, in this era of structural genomics, there should be major continued emphasis on completing structural information for important metabolic pathways. This will require improved efforts to obtain structures for enzyme complexes with appropriate cofactors, substrates or substrate analogs, as well as with inhibitors and regulators of activity. Then and only then will we have complete structural knowledge and facilitated structure-based drug design efforts. Structural genomics efforts promise to provide structural data in a high-throughput mode. However, we need to ensure that much of this focus is placed on completing the picture of metabolic pathways and enzyme active sites.

 

The availability of the human genomic sequence is changing the way in which biological questions are addressed. Based on the prediction of genes from nucleotide sequences, homologies among their encoded amino acids can be analyzed and used to place them in distinct families. This serves as a first step in building hypotheses for testing the structural and functional properties of previously uncharacterized paralogous genes. As genomic information from more organisms becomes available, these hypotheses can be refined through comparative genomics and phylogenetic studies. Instead of the traditional single-gene approach in endocrine research, we are beginning to gain an understanding of entire mammalian genomes, thus providing the basis to reveal subfamilies and pathways for genes involved in ligand signaling. The present review provides selective examples of postgenomic approaches in the analysis of novel genes involved in hormonal signaling and their chromosomal locations, polymorphisms, splicing variants, differential expression, and physiological function. In the postgenomic era, scientists will be able to move from a gene-by-gene approach to a reconstructionistic one by reading the encyclopedia of life from a global perspective. Eventually, a community-based approach will yield new insights into the complexity of intercellular communications, thereby offering us an understanding of hormonal physiology and pathophysiology. Many cellular signaling pathways ultimately control specific patterns of gene expression in the nucleus through a variety of signal-regulated transcription factors, including nuclear hormone receptors. The advent of genomic technologies for examining signal-regulated transcriptional responses and transcription factor binding on a genomic scale has dramatically increased our understanding of the cellular programs that control hormonal signaling and gene regulation. Studies of transcription factors, especially nuclear hormone receptors, using genomic approaches have revealed novel and unexpected features of hormone-regulated transcription, and a global view is beginning to emerge.

 

Source References:

 

http://pediatrics.aappublications.org/content/26/3/476.abstract

 

http://www.ncbi.nlm.nih.gov/pubmed/13499378

 

http://endo.endojournals.org/content/54/5/591.long

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC528661/

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196745/

 

http://www.ncbi.nlm.nih.gov/pubmed/11114510

 

http://www.ncbi.nlm.nih.gov/pubmed/23516625

 

http://www.annualreviews.org/doi/abs/10.1146/annurev.bi.50.070181.002341

 

http://www.sciencedirect.com/science/article/pii/S0016648098971258#

 

http://www.interactive-biology.com/3931/basics-of-hormone-classification/

 

http://en.wikipedia.org/wiki/Category:Hormones_by_chemical_structure

 

http://www.annualreviews.org/doi/abs/10.1146/annurev-physiol-021909-135840

 

http://www.ncbi.nlm.nih.gov/pubmed/16423812

 

http://edrv.endojournals.org/content/23/3/381.full.pdf

 

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