Methionine (Met), an essential amino acid taken from dietary proteins, is condensed with ATP by methionine adenosyltransferase (MAT) to form S-adenosylmethionine (SAM). Role of CBS and other enzymes in the regulation of mammalian sulfur amino acid metabolism. The current understanding of the role of CBS in mammalian sulfur amino acid metabolism (as well as the cooperative role of the other H 2S producing enzymes) is depicted in Figure 1. In fact, one of the current official names of CBS is “L-serine hydro-lyase (adding homocysteine L-cystathionine-forming)”. The multiple enzymatic processes CBS catalyzes were gradually discovered by multiple investigators these reactions (see also below) are also illustrated by the multiple names the enzyme had in the early years-such as β-thionase, cysteine synthase, L-serine hydro-lyase (adding homocysteine), methylcysteine synthase, and serine sulfhydrase. Cystathionine- β-synthase (CBS) is the first (and rate-limiting) enzyme in the transsulfuration pathway. The various enzyme(s) involved in transsulfuration reactions have been identified in the late 1960s through the discovery of several different reactions these enzymes catalyze (see below). Moreover, the discovery that transsulfuration is associated with the biogenesis of H 2S was not followed up further (neither by the du Vigneaud group, nor by others) the field had to wait many decades for the appreciation of the biological importance of this reaction. However, in du Vigneaud’s time, the field of biochemistry was not advanced enough to identify specific enzymes responsible for these reactions. In this experiment, liver homogenates were used to measure the formation of cysteine from homocysteine and serine, and H 2S formation was noted as a side reaction. Importantly, during his studies focusing on the interconversion of sulfur-containing amino acids, du Vigneaud (together with Francis Birkley) published a paper in 1942, which also noted the formation of the gas hydrogen sulfide (H 2S) from some of these reactions. However, for simplicity, in the current article we will use term “transsulfuration” to designate the mammalian system of homocysteine to cysteine conversion. Du Vigneaud initially simply termed the process as “transsulfuration” subsequently the terminology has been revised such that “transsulfuration” is now used to describe the bacterial system and “reverse transsulfuration” is the official term for the mammalian process. It was du Vigneaud who realized that a mammalian metabolic pathway involving the interconversion of cysteine and homocysteine exists he was also the scientist who discovered and named the intermediate of the reaction: cystathionine. His work (which started at Washington University, and continued at Cornell University) focused on the oxidation of sulfur-containing amino acids in various mammalian tissues (and subsequently in live animals as well). Transsulfuration was originally discovered by Vincent du Vigneaud in the 1930s and 1940s. We distinguish two transsulfuration pathways: the “forward transsulfuration pathway” (the bacterial pathway, which involves the transfer of the thiol group from cysteine to homocysteine) and the “reverse transsulfuration pathway” (the mammalian pathway, which involves the transfer of the thiol group from homocysteine to cysteine). The transsulfuration pathway is an important metabolic pathway in which the interconversion of cysteine and homocysteine occurs through the intermediate cystathionine. 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. 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. 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. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H 2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease.
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