SULFUR AMINO ACID METABOLISM: Pathways for Production and Removal of Homocysteine and Cysteine

Abstract

Tissue concentrations of both homocysteine (Hcy) and cysteine (Cys) are maintained at low levels by regulated production and efficient removal of these thiols. The regulation of the metabolism of methionine and Cys is discussed from the standpoint of maintaining low levels of Hcy and Cys while, at the same time, ensuring an adequate supply of these thiols for their essential functions. S-Adenosylmethionine coordinately regulates the flux through remethylation and transsulfuration, and glycine N-methyltransferase regulates flux through transmethylation and hence the S-adenosylmethionine/S-adenosylhomocysteine ratio. Cystathionine beta-synthase activity is also regulated in response to the redox environment, and transcription of the gene is hormonally regulated in response to fuel supply (insulin, glucagon, and glucocorticoids). The H2S-producing capacity of cystathionine gamma-lyase may be regulated in response to nitric oxide. Cys is substrate for a variety of anabolic and catabolic enzymes. Its concentration is regulated primarily by hepatic Cys dioxygenase; the level of Cys dioxygenase is upregulated in a Cys-responsive manner via a decrease in the rate of polyubiquitination and, hence, degradation by the 26S proteasome.

Hydrogen sulfide as an oxygen sensor

“…CBS, CSE, and CAT are pyridoxal 5¢ phosphate-dependent, enzymes. S-adenosylmethionine allosterically activates CBS (152) and although CBS contains a heme group that can be inhibited by CO, neither nitric oxide (NO) nor O 2 appears effective at physiological concentrations (4). CSE and both cytosolic and mitochondrial CAT activity are inhibited by calcium, independent of calmodulin (104,105).…”

“…In fact, it is not clear why most vertebrates, especially terrestrial ones, would be bothered with this pathway at all, except that it may be an important avenue for regeneration of H 2 S during hypoxia (124). A number of reviews (69,73,121,152,154) provide additional details of H 2 S metabolism.…”

The amino acid composition of tissue protein is affected by the total sulfur amino acid supply in growing pigs

“…As a semi-indispensable AA, Cys can be synthesized from Met through the transsulfuration pathway, whereas Met must be supplied by the diet (Chung and Baker, 1992). Cysteine is a constituent of glutathione, a major cellular antioxidant, and also serves as a precursor for taurine and co-enzyme A (Stipanuk, 2004).…”

Impairments in pyridoxine-dependent sulphur amino acid metabolism are highly sensitive to the degree of vitamin B6 deficiency and repletion in the pig

“…As a clearer picture develops of the role that elevated homocysteine concentrations play in the risk for chronic disease development in humans, it is important not to lose sight of the fundamental importance of this amino acid in serving as the sole source of sulphur for the endogenous synthesis of cysteine. De novo synthesis of cysteine, through the transsulphuration pathway, represents the primary route for the oxidation of the carbon skeleton of methionine, and is therefore an important component in the control of plasma and tissue methionine levels (Blom et al, 1989;Storch et al, 1990;Stipanuk, 2004). Cysteine synthesis, besides being important for providing a substrate for protein synthesis, is crucial for the regulation of the availability of the biological antioxidant glutathione (Hunter and Grimble, 1997), as well as other sulphur-containing compounds (e.g., taurine).…”