Transsulfuration

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.

Abstract: BACKGROUND: Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. OBJECTIVE: Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. METHODS: Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. RESULTS: The metabolic results indicated that plasma methionine and the ratio of Sadenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-Stransferase (GST M1). CONCLUSION: We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.

Abstract: Two pathways, the methionine cycle and transsulfuration, account for virtually all methionine metabolism in mammals. Every tissue possesses the methionine cycle. Therefore, each can synthesize AdoMet, employ it for transmethylation, hydrolyze AdoHcy, and remethylate homocysteine. Transsulfuration, which occurs only in liver, kidney, small intestine and pancreas, is the means for catabolizing homocysteine. Liver has a unique isoenzyme of MAT that allows the utilization of excess methionine for the continued synthesis of AdoMet. Metabolic regulation is based on the distribution of available homocysteine between remethylation and conversion to cystathionine. The tissue content of the enzymes and their inherent kinetic properties provide the basis for the regulatory mechanism. The effector properties of the metabolites AdoMet, AdoHcy and methylTHF are of particular relevance.