Homocysteine (Hcy) metabolism is at the cross-roads of several pathways and is itself a byproduct of the de novo pathway of the methionine metabolic cycle. Hcy can be methylated to methionine via the cobalamin-dependent and independent pathways. The first is the predominant reaction in most tissues and is carried out by methionine synthase (Mtr). The requirement for the 1 carbon (1C) donor 5-methyl tetrahydrofolate and the generation of tetrahydrofolate (THF) in the reaction, engages folate meta
bolism whose components are the folate cycle and the folate mediated one-carbon metabolic pathways. The cobalamin-independent, betaine-dependent pathway is the major route of Hcy remethylation in the liver. The choline derived betaine is the methyl donor in the reaction catalyzed by the zinc metalloprotein Bhmt with dimethylglycine (DMG) as a by-product. The other route of Hcy metabolism is the transsulfuration pathway which results in the production of cysteine and other metabolites downstream of it. The product of the first reaction in the methionine cycle - S-adenosylmethionine, known as AdoMet or SAM, inhibits the folate-dependent methylation and activates cystathione-beta-synthase (Cbs), the first enzyme in the transsulfuration pathway. This way, Hcy metabolism is channeled to remethylation when methionine/AdoMet levels are low, whereas when methionine/AdoMet levels are high, it is channeled to transsulfuration. The remethylation pathways converge on the methionine cycle and lead to homocysteine production; the transsulfuration pathway irreversibly degrades Hcy. The first two reactions in the transsulfuration pathway are carried out by pyridoxal 5-phosphate (PLP/vitamin B6)-dependent enzymes. The first reaction involves the condensation of Hcy and serine by cystathione-beta-synthase (Cbs) to produce cystathione. As mentioned, AdoMet activates Cbs; it also promotes its stability. Note that the human and Drosophila enzymes also contain a heme cofactor. In the second reaction, cystathione is hydrolyzed by Cth (cystathione gamma-lyase) to form cysteine which now contains the sulfur atom from Hcy, along with ammonium and alpha-ketobutyrate containing the amino group and the carbon chain of Hcy, respectively. Cysteine is the rate-limiting precursor for the synthesis of the powerful anti-oxidant glutathione. Cysteine can be further catabolized via both non-oxidative desulfuration and oxidative routes whose metabolites can be fueled into other pathways or converted to end-products that can be excreted. The non-oxidative route involves several and rather non-specific reactions that Cbs and Cth carry out and can produce hydrogen sulfide (H2S). Elevated levels of H2S are toxic due to the ability to react with metal- or disulfide-containing proteins. However, it can act as a signaling molecule with roles in the heart, brain and smooth muscle. Sulfide/sulfur is oxidized to sulfite and then to sulfate via a number of enzyme catalyzed reactions in the mitochondria (details not shown). In the oxidative route of cysteine catabolism, the first step involves the irreversible oxidation of cysteine to cysteinsulfinate, also known as cysteinsulfinic acid (CSA) or 3-sulfinoalanine, catalyzed by cysteine dioxygenase, Cdo1. Cdo1 is highly expressed in liver with appreciable amounts also found in brain, kidney, pancreas, lung and adipose tissue. Cdo1 is a non-heme mononuclear iron-containing metalloenzyme belonging to the cupin superfamily whose activity is regulated by the formation of a thioether cross-link between Cys93 and Tyr157 acting as a cofactor that enhances the enzyme's activity. The crystal structures of mammalian enzymes have been solved by X-ray crystallography and they provide important mechanistic insights. Cysteinsulfinate can be decarboxylated to hypotaurine by cysteine sulfinic acid decarboxylase (Csad) and further oxidized to taurine in a step whose enzymatic or non-enzymatic nature remains to be determined. Alternatively, cysteinesulfinate may be transaminated to 3-sulfinylpyruvate which spontaneously dissociates to pyruvate and sulfur dioxide (SO2). The latter is hydrated to sulfite and then oxidized to sulfate in the mitochondria, as mentioned above. The pathways of methionine, homocysteine and folate metabolism are intimately interconnected. Defects in enzymes within these pathways have been associated with several disorders and conditions. To see the ontology report for Gviewer, annotations and download, click here ...(less)