3-mercaptopyruvate Transferase Research Articles

Hydrogen Sulfide Is an Endogenous Regulator of Aging in Caenorhabditis elegans

To investigate the role of endogenous hydrogen sulfide (H2S) in the control of aging and healthspan of Caenorhabditis elegans. We show that the model organism, C. elegans, synthesizes H2S. Three H2S-synthesizing enzymes are present in C. elegans, namely cystathionine γ lyase (CSE), cystathionine β synthetase, and 3-mercaptopyruvate transferase (MPST or 3-MST). Genetic deficiency of mpst-1 (3-MST orthologue 1), but not cth-2 (CSE orthologue), reduced the lifespan of C. elegans. This effect was reversed by a pharmacological H2S donor (GYY4137). GYY4137 also reduced detrimental age-dependent changes in a range of physiological indices, including pharyngeal contraction and defecation. Treatment of C. elegans with GYY4137 increased the expression of several age-related, stress response, and antioxidant genes, whereas MitoSOX Red fluorescence, indicative of reactive oxygen species generation, was increased in mpst-1 knockouts and decreased by GYY4137 treatment. GYY4137 additionally increased the lifespan in short-lived mev-1 mutants with elevated oxidative stress and protected wild-type C. elegans against paraquat poisoning. The lifespan-prolonging and health-promoting effects of H2S in C. elegans are likely due to the antioxidant action of this highly cell-permeable gas. The possibility that novel pharmacological agents based on the principle of H2S donation may be able to retard the onset of age-related disease by slowing the aging process warrants further study. Our results show that H2S is an endogenous regulator of oxidative damage, metabolism, and aging in C. elegans and provide new insight into the mechanisms, which control aging in this model organism.

EP03 Therapeutic outlook for hydrogen sulfide donors

Considerable evidence has accumulated in recent years suggesting that H 2 S, synthesised from l -cysteine via cystathionine γ lyase (CSE) or cystathionine β synthase (CBS) or from 3-mercaptopyruvate via 3-mercaptopyruvate transferase (3-MST), plays a significant part in a range of physiological and/or pathophysiological processes. The possibility that either manipulating endogenous H 2 S biosynthesis or using H 2 S donor drugs may lead to new therapeutic entities was raised several years ago (e.g. [1] ). Increasingly, H 2 S is being thought of as a cytoprotective agent which restores physiological function in diseased cells or organ systems and hence interest has centred on identifying novel H 2 S donors. To date, a number of H 2 S donors have been characterized. These include thiones such as 5-( p -hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), cysteine derivatives such as S-allylcysteine (SAC) and S-propargyl-cysteine (S-SPRC), GYY4137 (morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate), H 2 S-releasing derivatives of non-steroidal anti-inflammatory drugs (NSAID) such as S-diclofenac and, recently, a nitric oxide (NO) and H 2 S-releasing derivative of aspirin. In addition, sulfide salts such as sodium hydrosulfide (NaHS) also release H 2 S. Other H 2 S-releasing drugs are no doubt in the pipeline. Potential applications of some or all of these compounds include such diverse conditions as hypertension, cardiac failure, ischemic reperfusion injury, acute and chronic inflammation, cancer and even to promote healthy aging. For example, GYY4137 reduces knee joint swelling in mice injected with Freund’s adjuvant [2] and is anti-tumor in the mouse [3] . Thus, H 2 S donors have shown early promise in a range of therapeutic areas. The further development of H 2 S donors presents a number of difficulties. For example, equating plasma concentration of released H 2 S from such donors with biological activity in an animal model (or in man) is problematic since, not only is H 2 S rapidly metabolized to an array of products, but current techniques to measure the concentration of this endogenous gas are likely insufficiently sensitive or selective. In addition, efficacy would be better correlated with H 2 S concentration at the site where the gas produces its biological effect (not plasma) which may be extracellular or even intracellular perhaps close to or in mitochondria. Further work is also needed to assess the cell permeability of H 2 S donors in order to determine whether they ‘carry’ H 2 S into cells thereby ‘loading’ the cell with the gas. This presentation will provide an overview of the potential for H 2 S donors in the clinic.