Cystathionine β-synthase: Difference between revisions
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== Disease == | == Disease == | ||
'''The Metabolic Pathway of Homocysteine''' | |||
The metabolism of L-methionine comprises two intersecting pathways: the synthesis pathway via the S-adenosyl methionine cycle (SAM cycle) and the transsulfuration pathway leading to glutathione synthesis. At the intersection of these sits homocysteine (Hcy), a non-proteinogenic amino acid whose elevated plasma levels (eHcy) has been observed in several medical conditions indicating the toxic effect of this chemical substance and need for rigorous control of its amount. | |||
The Hcy concentrations are maintained dynamically by either a transsulfuration or remethylation pathway provided by different enzymes. | |||
The remethylation reaction is carried out by two enzymes. Methionine synthase, with vitamin B12 as a cofactor, remethylates Hcy back to methionine. Methylene tetrahydrofolate (MTHF) derived from tetrahydrofolate (THF) by methylenetetrahydrofolate reductase (MTHFR) is used as a donor of the methyl group so folate is also required for this reaction. The remethylation pathway is favored under conditions where methionine levels are low, resulting in conservation of this metabolite. | |||
When methionine levels are high, transsulfuration dominates. The transsulfuration pathway catalyzes the conversion of homocysteine to cysteine, and is the only de novo pathway for cysteine production in mammals. In the first step, homocysteine is condensed with serine to form cystathionine, the reaction is catalyzed by cystathionine β-synthase (CBS), and is dependent on vitamin B6 as an enzymatic cofactor. In the second step, cystathionine is cleaved by cystathionase (CTH), also known as cystathionine γ-lyase (CSE), to form cysteine and α-ketobutyrate. Cysteine is used in synthesis of downstream products such as glutathione (GSH), taurine, and hydrogen sulfide (H2S). | |||
Hcy is a precursor of S-adenosyl-L-methionine (AdoMet), a methyl group donor in a large number of biochemical reactions, and a metabolite of S-adenosyl-L-homocysteine (AdoHcy). The ratio of AdoMet to AdoHcy is defined as the methylation potential (MP). The two pathways are coordinated by AdoHcy, which acts as an allosteric inhibitor of the MTHFR reaction and as an activator of CBS. | |||
[[Image:Homocysteine metabolic pathway.png|600px|left Homocysteine metabolic pathway. Homocysteine sits at the intersection of the remethylation and transsulfuration pathways. In the remethylation pathway, THF is converted to N5,N10-methylene tetrahydrofolate and then to MTHF by methylenetetrahydrofolate reductase (Mthfr). The methyl group is donated to Hcy and in the presence of methionine synthase (Mtr), and B12 is converted to methionine. Methionine is used in many methyl transfer reactions. When the diet is replete with methionine, Hcy is converted, via the transsulfuration pathway, to cystathionine by cystathionine β-synthase (Cbs) and then converted to cysteine via the action of cystathionase (Cth, Cse) in the presence of B6. Cysteine is converted to several beneficial downstream products.]] | |||
Among the pathological states that have been mentioned in relation with eHcy are cardiovascular disorders, atherosclerosis, myocardial infarction, stroke, minimal cognitive impairment, dementia, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, epilepsy, and eclampsia (2). All these observations indicates that Hcy, and especially eHcy, exerts direct toxic effects on both the vascular and nervous systems. | |||
Mutations in the gene encoding CBS resulting in abnormalities of its function with all the consequences are usually referred as of homocystinuria. The mutations can alter either mRNA or enzyme stability, activity, binding of PLP and heme, or impair allosteric regulation (3). To date there have been over 100 mutations described in this gene (4). | |||
Deficiency in the activity of the enzyme caused by insufficient supplementation of enzymatic cofactores leads to accumulation of L-homocysteine, hyperhomocysteinemia, with similar but moderate indications like homocystinuria. | |||
Involvement in such a wide number of apparently unrelated diseases may be caused by affecting a very basic biological process central to a variety of diseases. There are two major hypotheses about how this could be accomplished. | |||
The first one has centered on the relationship between homocysteine and oxidative stress. Homocysteine itself has been shown to cause increased oxidative stress on cells, both through direct effects (e.g., the production of hydrogen peroxide by oxidation of homocysteine to homocystine) and indirect effects (e.g., reduction of glutathione peroxidase). In addition, it is estimated that as much as 50% of the cellular antioxidant glutathione is produced from homocysteine by conversion through the transsulfuration pathway. | |||
A second popular hypothesis suggests that eHcy affects the control of biologically important methylation reactions by causing a build-up of S-adenosyl-L-homocysteine (AdoHcy) which is a competitive inhibitor of S-adenosyl-L-methionine (AdoMet) binding for methyltransferase enzymes. As methyltransferases are involved in a variety of important biological processes, inhibition of this class of enzymes could have extremely diverse effects on the organism (5). | |||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||