[SCAN] 'Stinking' biochemistry: Hydrogen sulfide metabolism in human (patho)physiology
João B. Vicente, Structural Genomics
| When |
16 Mar, 2016
from
12:00 pm to 01:00 pm |
|---|---|
| Where | Auditorium |
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SCAN
Title: 'Stinking' biochemistry: Hydrogen sulfide metabolism in human (patho)physiology
Speaker: João B. Vicente
Affiliation: Structural Genomics, Macromolecular Crystallography Unit
Background:
Hydrogen sulfide (H2S) has emerged in the past few decades from a toxic poison to a key signaling molecule in human physiology, similarly to its historical ‘predecessors’ nitric oxide (NO) and carbon monoxide (CO). H2S regulates multiple physiological processes such as vasorelaxation, angiogenesis, bioenergetics/respiration, cell survival and proliferation, most of its action resulting from sulfhydration of cysteine residues in the target proteins.
H2S is endogenously synthesized by three human enzymes, all of them related to cysteine metabolism, and it’s catabolized in the mitochondria by a sulfide oxidizing unit composed of four enzymes. The gut microbiota is another relevant H2S source in that particular part of the body.
Due to its intrinsic reactivity and highly diffusible nature, disturbed H2S levels associated with a dysfunctional metabolism are at the core of numerous pathologies, from cardiovascular and neurodegenerative disease to cancer.
Aims and Rationale:
Several lines of evidence point to H2S metabolism enzymes to mediate the crosstalk between the ‘gasotransmitters’ H2S, CO and NO, and to be modulated by several endogenous signaling molecules, with relevant (patho)physiological implications. This project aims to i) dissect the structural and biochemical implications of such interactions and modifications, and ii) carry out a systematic search for compounds with modulatory effect towards H2S metabolism enzymes, with pharmacological potential. Different cell models of intimately related diseases, such as colorectal cancer, will be employed to validate the hit compounds.
Results/Examples:
The H2S-synthesizing human enzyme cystathionine β-synthase (CBS) is inhibited by NO and CO, via a non-catalytic regulatory heme moiety. A thorough spectroscopic and kinetic analysis was carried out to further understand the molecular details of this regulatory mechanism. Moreover, s-adenosyl-l-methionine, the methyl donor in virtually all methylation reactions in the cell and an allosteric activator of CBS, puzzlingly elicits CBS inhibition by CO and NO, which illustrates the intricate regulation of H2S production, and offers a line of prospective therapeutic interventions.
