Oligomeric status of human cystathionine beta‐synthase modulates AdoMet binding

Pey, Ángel L.; Martínez-Cruz, L.A.; Kraus, Jan P.; Majtán, Tomáš

doi:10.1002/1873-3468.12488

Cited by 12 publications

(22 citation statements)

References 20 publications

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“…In 1984 Skovby, Kraus, and Rosenberg have noticed that —in addition to the regular 63 kDa Mw form of CBS – liver tissue also contains a 48 kDa form of CBS, which appears to be the product of limited proteolysis [ 32 ]. This form of the enzyme has been designated early on as the “evolutionarily conserved active core of CBS” [ [33] , [34] , [35] ]. Subsequent studies demonstrated the appearance of this truncated form in cells and animals exposed to pro-inflammatory conditions [ 36 ] or to hypoxia [ 37 ].…”

Section: Cbsmentioning

confidence: 99%

Emerging roles of cystathionine β-synthase in various forms of cancer

Ascenção¹,

Szabó²

2022

Redox Biology

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Section: Cbsmentioning

confidence: 99%

Emerging roles of cystathionine β-synthase in various forms of cancer

Ascenção¹,

Szabó²

2022

Redox Biology

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“…Strikingly, a total binding capacity of six SAM molecules per CBS tetramer was found, each tetramer binding two SAMs with high affinity (with a Kd ~10 nM) and four SAMs with low affinity (Kd ~370 nM). Binding isotherms were consistent with both types of sites binding independently (noncooperatively) the ligand, and attempts to alternatively use a model with a total binding capacity of four dependent sites with negative cooperativity yielded poor results (Pey et al 2013(Pey et al , 2016b. Despite the inherent complexity of SAM binding to tetrameric CBS [with up to 15 different ligation states, many of them degenerate, and their population strongly dependent on SAM concentration (Pey et al 2013)], thermodynamic analyses of SAM binding combined with functional assays support different and independent functions for both types of sites.…”

Section: Binding Of Sam By Cbs: Stabilization Of the Enzymementioning

confidence: 99%

“…10) could be found or designed in order to independently modulate CBS activity and kinetic stability. Ligand-induced kinetic stabilization of the regulatory domain (Pey et al 2013;Majtan et al 2016;Pey et al 2016b) of a missense CBS mutant would result in increased intracellular levels of the protein. For example, Pey et al found out that the half-life for irreversible denaturation of the regulatory domain in CBS mutants is as much as 200-fold lower compared to the WT, thus making it extremely kinetically unstable (Pey et al 2013).…”

Section: Activators or Kinetic Stabilizers Targeting Cbs Regulatory D...mentioning

confidence: 99%

Potential Pharmacological Chaperones for Cystathionine Beta-Synthase-Deficient Homocystinuria

Majtán

Pey

Giménez-Mascarell

et al. 2017

Handbook of Experimental Pharmacology

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Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acid metabolism. HCU is caused by a deficiency in enzymatic degradation of homocysteine, a toxic intermediate of methionine transformation to cysteine, chiefly due to missense mutations in the cystathionine beta-synthase (CBS) gene. As with many other inherited disorders, the pathogenic mutations do not target key catalytic residues, but rather introduce structural perturbations leading to an enhanced tendency of the mutant CBS to misfold and either to form nonfunctional aggregates or to undergo proteasome-dependent degradation. Correction of CBS misfolding would represent an alternative therapeutic approach for HCU. In this review, we summarize the complex nature of CBS, its multi-domain architecture, the interplay between the three cofactors required for CBS function [heme, pyridoxal-5'-phosphate (PLP), and S-adenosylmethionine (SAM)], as well as the intricate allosteric regulatory mechanism only recently understood, thanks to advances in CBS crystallography. While roughly half of the patients respond to treatment with a PLP precursor pyridoxine, many studies suggested usefulness of small chemicals, such as chemical and pharmacological chaperones or proteasome inhibitors, rescuing mutant CBS activity in cellular and animal models of HCU. Non-specific chemical chaperones and proteasome inhibitors assist in mutant CBS folding process and/or prevent its rapid degradation, thus resulting in increased steady-state levels of the enzyme and CBS activity. Recent interest in the field and available structural information will hopefully yield CBS-specific compounds, by using high-throughput screening and computational modeling of novel ligands, improving folding, stability, and activity of CBS mutants.

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“…In terms of structure, CBS is a unique heme-containing pyridoxal 5′-phosphate (PLP)-dependent enzyme that is allosterically activated by s -adenosylmethionine (AdoMet or SAM) [ 24 , 25 ]. The full-length human CBS is a homotetramer consisting by 63 kDa subunits, with each subunit comprising 551 residues [ 26 ]. CBS adopts a three-domain structure encompassing an n -terminal heme-binding domain, a central catalytic domain (PLP cavity) which is accessible only via a narrow channel, and a smaller c -terminal allosteric regulatory domain (CBS motif, Bateman module) [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

et al. 2020

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Cystathionine β-synthase (CBS) is a key enzyme in the production of the signaling molecule hydrogen sulfide, deregulation of which is known to contribute to a range of serious pathological states. Involvement of hydrogen sulfide in pathways of paramount importance for cellular homeostasis renders CBS a promising drug target. An in-house focused library of heteroaromatic compounds was screened for CBS modulators by the methylene blue assay and a pyrazolopyridine derivative with a promising CBS inhibitory potential was discovered. The compound activity was readily comparable to the most potent CBS inhibitor currently known, aminoacetic acid, while a promising specificity over the related cystathionine γ-lyase was identified. To rule out any possibility that the inhibitor may bind the enzyme regulatory domain due to its high structural similarity with cofactor s-adenosylmethionine, differential scanning fluorimetry was employed. A sub-scaffold search guided follow-up screening of related compounds, providing preliminary structure-activity relationships with respect to requisites for efficient CBS inhibition by this group of heterocycles. Subsequently, a hypothesis regarding the exact binding mode of the inhibitor was devised on the basis of the available structure-activity relationships (SAR) and a deep neural networks analysis and further supported by induced-fit docking calculations.

show abstract

Oligomeric status of human cystathionine beta‐synthase modulates AdoMet binding

Cited by 12 publications

References 20 publications

Emerging roles of cystathionine β-synthase in various forms of cancer

Emerging roles of cystathionine β-synthase in various forms of cancer

Potential Pharmacological Chaperones for Cystathionine Beta-Synthase-Deficient Homocystinuria

Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

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