Current Structural Knowledge on Cystathionine β‐Synthase, a Pivotal Enzyme in the Transsulfuration Pathway

Abstract

Cystathionine β‐synthase (CBS), the first enzyme of the reverse transsulfuration pathway, catalyses the pyridoxal‐5′‐phosphate (PLP)‐dependent β‐replacement reaction that condenses l ‐serine with L‐homocysteine to yield cystathionine and water. Besides this canonical reaction and using cysteine and homocysteine as substrates, CBS can also efficiently produce hydrogen sulfide (H 2 S) through alternative β‐replacement and β‐elimination processes. The structural information on the full‐length enzyme has remained elusive for decades and is still very scarce, but some advances in the recent years have uncovered its peculiar modular architecture, provided a glimpse of its conformational landscape and revealed some of the reaction intermediates formed during the catalysis. All these data have helped comprehend, at least partially, the regulatory mechanisms and the catalytic abilities of the enzyme across different organisms. This article aims to overview the current information on the CBS structure from its most sophisticated variants found in mammals to its simplest homologs in bacteria. A more detailed understanding of CBS structure and function is needed, which could subsequently serve as a basis for the development of drugs to treat human diseases, such as CBS‐deficient homocystinuria, Alzheimer diseases and some cancers, as well as of new antibiotics against multidrug‐resistant pathogenic bacteria. Key Concepts Reverse transsulfuration is a two‐step metabolic route that allows the conversion of the essential amino acid methionine into cysteine. This process generates hydrogen sulfide and impedes the accumulation of the toxic intermediate homocysteine. Hydrogen sulfide is an important gasotransmitter involved in physiological functions such as neuroprotection and the regulation of blood pressure. Homocystinuria consists of the abnormal accumulation of homocysteine, and is an inherited disorder due to the deficient activity of CBS. This pathology causes vascular thromboses, skeletal defects, mental retardation, and even early death. The three‐dimensional structure of CBS provides a suitable template to develop drugs to treat homocystinuria and related pathologies in humans. The comparative structural analysis of the CBS enzymes from different organisms are key to intervene in their sulfur metabolism, and thus represents a potential therapeutic approach against pathogens.

Structural basis of the inhibition of cystathionine γ‐lyase from Toxoplasma gondii by propargylglycine and cysteine

“…Reverse transsulfuration involves two consecutive steps catalyzed by two distinct enzymes. The first is cystathionine β‐synthase (CBS; recently reviewed in González‐Recio et al, n.d.), which catalyzes a β‐replacement reaction in which the hydroxyl group of l ‐serine is replaced by HCys, yielding Cth and H 2 O. The second is cystathionine γ‐lyase (CGL), which facilitates the α,γ‐elimination of Cth into Cys, α‐ketobutyrate (KTB), and ammonia (Figure 1, reaction 1).…”

Insights into Domain Organization and Regulatory Mechanism of Cystathionine Beta-Synthase from Toxoplasma gondii

“…CBS adopts a multidomain architecture that differs across organisms and is best exemplified in the well-studied human enzyme [ 2 , 3 , 4 , 5 ]. Human CBS (HsCBS) contains: the N-terminal heme-binding region, which was suggested to function in enzyme folding and/or redox sensing [ 6 , 7 , 8 , 9 ]; a central catalytic core which is highly conserved in the fold type II PLP enzymes [ 2 , 10 ]; and the C-terminal S -adenosyl-L-methionine (AdoMet) binding regulatory domain [ 11 , 12 , 13 , 14 ].…”

“…Human CBS (HsCBS) contains: the N-terminal heme-binding region, which was suggested to function in enzyme folding and/or redox sensing [ 6 , 7 , 8 , 9 ]; a central catalytic core which is highly conserved in the fold type II PLP enzymes [ 2 , 10 ]; and the C-terminal S -adenosyl-L-methionine (AdoMet) binding regulatory domain [ 11 , 12 , 13 , 14 ]. The binding of the allosteric modulator AdoMet causes a shift in the enzyme conformation from a basket-shaped low activity basal state [ 15 ] to a marine mooring bollard-shaped more active conformation [ 5 , 16 ]. In contrast, only a single conformation which is constitutively activated has been found in less evolved organisms, such as Drosophila melanogaster (DmCBS) and Apis mellifera (AmCBS).…”