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.
Highlights
The transsulfuration pathway is an important metabolic pathway in which the interconversion of cysteine and homocysteine occurs through the intermediate cystathionine
For simplicity, in the current article we will use term “transsulfuration” to designate the mammalian system of homocysteine to cysteine conversion. During his studies focusing on the interconversion of sulfur-containing amino acids, du Vigneaud published a paper in 1942, which noted the formation of the gas hydrogen sulfide (H2S) from some of these reactions [2]
The multiple enzymatic processes cystathionine beta-synthase (CBS) catalyzes were gradually discovered by multiple investigators [3,4,5,6,7,8,9,10]; these reactions are illustrated by the multiple names the enzyme had in the early years—such as β-thionase, cysteine synthase, L-serine hydro-lyase, methylcysteine synthase, and serine sulfhydrase
Summary
The transsulfuration pathway is an important metabolic pathway in which the interconversion of cysteine and homocysteine occurs through the intermediate cystathionine. For simplicity, in the current article we will use term “transsulfuration” to designate the mammalian system of homocysteine to cysteine conversion During his studies focusing on the interconversion of sulfur-containing amino acids, du Vigneaud (together with Francis Birkley) published a paper in 1942, which noted the formation of the gas hydrogen sulfide (H2S) from some of these reactions [2]. In addition to its two substrates (homocysteine and serine) three additional ligands: pyridoxal-5 -phosphate (PLP, the active form of vitamin B6), forming a Schiff base with Lys119, S-adenosylmethionine (SAM; known as AdoMet, an allosteric activator), and heme, the function of which has been subject to intensive debate for many decades (see below for additional details). At the image of its diverse distribution and large potential regulators list (including H2S itself), CBS regulation is extremely complex
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