Serine hydroxymethyltransferase (SHMT) and Cystathionine β-synthase (CBS) (SHMT/CBS)

Serine hydroxymethyltransferase (SHMT) and Cystathionine β-synthase (CBS) are two distinct pyridoxal 5'-phosphate (PLP)-dependent enzymes that play pivotal roles in cellular metabolism. SHMT, particularly the mitochondrial isoform SHMT2, is a key enzyme in the one-carbon metabolism pathway, facilitating the conversion of serine to glycine and providing one-carbon units necessary for DNA synthesis and repair (UniProt P34897). Cystathionine β-synthase (CBS) is the rate-limiting enzyme in the transsulfuration pathway, converting homocysteine and serine into cystathionine, which is a precursor for cysteine and the gasotransmitter hydrogen sulfide (H2S) (UniProt P35520). Deficiencies in CBS lead to homocystinuria, a serious metabolic disorder, while its overexpression in certain cancers contributes to tumor growth via H2S signaling (PubMed: 25653181). Although both enzymes utilize serine as a substrate and are PLP-dependent, they are separate proteins encoded by different genes and are not typically considered a single therapeutic target. Experimental inhibitors like SHIN1 and SHIN2 target SHMT to disrupt cancer cell proliferation, whereas compounds like aminooxyacetic acid are used in research to inhibit CBS activity (PubMed: 28604678, 23690555). Targeting these enzymes offers therapeutic potential in oncology and metabolic diseases, though selectivity remains a challenge due to their shared reliance on the PLP cofactor.

Other names

SHMT1SHMT2CBSSerine aldolaseGlycine hydroxymethyltransferaseBeta-thionaseMethylcysteine synthase

Inhibition of enzymatic activity to disrupt one-carbon metabolism or hydrogen sulfide production.