Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition

Abstract

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used “CBS inhibitors” (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.

Alterations in One-Carbon Metabolism in Celiac Disease

“…Considering the transsulfuration pathway, the decreased concentration of cysteine and cystathionine in CD patients could be due to defects in the enzymes that participate in its biosynthesis. Thus, the step from homocysteine to cystathionine is mediated by cystathioninebeta-synthase (CBS; EC 4.2.1.22), and the conversion of cystathionine to cysteine is catalyzed by the enzyme cystathionine gamma-lyase or cystathionase (CTH; EC 4.4.1.1) [27][28][29]. Interestingly, both enzymes are cytoplasmic homotetramers that require vitamin B6 (pyridoxal phosphate) as a cofactor, and both are able to produce hydrogen sulfide (H2S), a gasotransmitter, by using cysteine [28][29][30][31].…”

Cystathionine-β-synthase affects organization of cytoskeleton and modulates carcinogenesis in colorectal carcinoma cells

“…Mechanism, how CBS can through cytoskeletal proteins affect tumors´ growth, proliferation and migration needs to be studied in detail. As stated by Zuhra et al [2] -"even when the involvement of CBS in a given biological process is undisputable, it is often di cult to determine if the observed biological effects related to CBS are, in fact, due to upstream alterations (e.g., homocysteine accumulation due to CBS inhibition), downstream alterations (e.g., lack of production of cytoprotective cystathione or H 2 S after CBS inhibition) or global cellular changes (e.g., alterations in cellular glutathione levels and compensatory changes in redox balance)". Likewise, protein-protein interaction should be taken into the consideration, regarding the function.…”

“…1,25-dihydroxyvitamin D3, hypoxia-inducible factors, estradiol-17b, etc. (for review see [2]), depending on a type of cells. Physiological role of CBS is still not completely clear, although detrimental effect on the cardiovascular system is evident [3].…”

Interplay of Enzyme Therapy and Dietary Management of Murine Homocystinuria

“…Classical homocystinuria (HCU; OMIM# 236200) is a rare inborn error of sulfur amino acid metabolism caused by substantially reduced or entirely missing cystathionine beta-synthase (CBS) activity [ 1 ]. Human CBS is a complex enzyme with intricate regulation responsible for the condensation of homocysteine (Hcy), a toxic intermediate of methionine (Met) metabolism, with serine to form cystathionine (Cth), thus directing the flux of organic sulfur irreversibly toward the biosynthesis of cysteine (Cys) [ 2 ] ( Figure 1 ). Consequently, a lack of CBS activity leads to extremely elevated plasma and tissue Hcy concentrations, which represent a biochemical hallmark of HCU.…”