6027-13-0Relevant articles and documents
Functional consequences of homocysteinylation of the elastic fiber proteins fibrillin-1 and tropoelastin
Hubmacher, Dirk,Cirulis, Judith T.,Miao, Ming,Keeley, Fred W.,Reinhardt, Dieter P.
, p. 1188 - 1198 (2010)
Homocystinuria caused by cystathionine-β-synthase deficiency represents a severe form of homocysteinemias, which generally result in various degrees of elevated plasma homocysteine levels. Marfan syndrome is caused by mutations in fibrillin-1, which is one of the major constituents of connective tissue microfibrils. Despite the fundamentally different origins, both diseases share common clinical symptoms in the connective tissue such as long bone overgrowth, scoliosis, and ectopia lentis, whereas they differ in others. Fibrillin-1 contains ～13% cysteine residues and can be modified by homocysteine. We report here that homocysteinylation affects functional properties of fibrillin-1 and tropoelastin. We used recombinant fragments spanning the entire fibrillin-1 molecule to demonstrate that homocysteinylation, but not cysteinylation leads to abnormal self-interaction, which was attributed to a reduced amount of multimerization of the fibrillin-1 C terminus. The deposition of the fibrillin-1 network by human dermal fibroblasts was greatly reduced by homocysteine, but not by cysteine. Furthermore, homocysteinylation, but not cysteinylation of elastin-like polypeptides resulted in modified coacervation properties. In summary, the results provide new insights into pathogenetic mechanisms potentially involved in cystathionine-β-synthase-deficient homocystinuria.
Identification of O-acetylhomoserine sulfhydrylase, a putative enzyme responsible for methionine biosynthesis in Clostridioides difficile: Gene cloning and biochemical characterizations
Kulikova, Vitalia V.,Revtovich, Svetlana V.,Bazhulina, Natalia P.,Anufrieva, Natalya V.,Kotlov, Mikhail I.,Koval, Vasiliy S.,Morozova, Elena A.,Hayashi, Hideyuki,Belyi, Yury F.,Demidkina, Tatyana V.
, p. 1815 - 1823 (2019)
O-acetylhomoserine sulfhydrylase (OAHS) is a pyridoxal 5′-phosphate-dependent enzyme involved in microbial methionine biosynthesis. In this study, we report gene cloning, protein purification, and some biochemical characteristics of OAHS from Clostridioides difficile. The enzyme is a tetramer with molecular weight of 185 kDa. It possesses a high activity in the reaction of L-homocysteine synthesis, comparable to reported activities of OAHSes from other sources. OAHS activity is inhibited by metabolic end product L-methionine. L-Propargylglycine was found to be a suicide inhibitor of the enzyme. Substrate analogue Nγ-acetyl-L-2,4-diaminobutyric acid is a competitive inhibitor of OAHS with Ki = 0.04 mM. Analysis of C. difficile genome allows to suggest that the bacterium uses the way of direct sulfhydrylation for the synthesis of L-methionine. The data obtained may provide the basis for further study of the role of OAHS in the pathogenic bacterium and the development of potential inhibitors.
COMPOSITONS AND METHODS FOR TREATING BRAIN INJURY
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A method for treating a hyperhomocysteinemic subject having cerebral ischemic stroke generally includes administering to the hyperhomocysteinemic subject, following cerebral stroke, a composition that includes an inhibitor or an antagonist of a GluN2A-containing N-methyl-D-aspartate receptor (NMDAR) in an amount effective to ameliorate at least one symptom or clinical sign of cerebral stroke.
Poly(S-ethylsulfonyl- l -homocysteine): An α-Helical Polypeptide for Chemoselective Disulfide Formation
Muhl, Christian,Sch?fer, Olga,Bauer, Tobias,R?der, Hans-Joachim,Barz, Matthias
, p. 8188 - 8196 (2018/10/31)
Homocysteine and cysteine are the only natural occurring amino acids that are capable of disulfide bond formations in peptides and proteins. The chemoselective formation of asymmetric disulfide bonds, however, is chemically challenging and requires an activating group combining stability against hard nucleophiles, e.g., amines, with reactivity toward thiols and soft nucleophiles. In light of these considerations, we introduced the S-alkylsulfonyl cysteines in our previous work. Here, we present the synthesis and ring-opening polymerization of S-ethylsulfonyl-l-homocysteine N-carboxyanhydrides. We demonstrate that the polymerization leads to narrowly distributed polypeptides (D= 1.1-1.3) with no detectable side reactions in a chain length regime from 11 to 165. In contrast to the already reported cysteine derivatives, poly(S-ethylsulfonyl-l-homocysteine)s do not form β-sheets, which reduce solubility and limit the degree of polymerization of poly(S-ethylsulfonyl-l-cysteine)s to 50. Instead, these polymers form α-helices as confirmed by circular dicroism (CD) experiments and infrared spectroscopy (FT-IR). In comparison to the cysteine derivatives, the α-helix formation leads to slightly faster polymerization kinetics (rate constants from 1.44 × 10-5 to 5.29 × 10-5 s-1). In addition, the ability for the chemoselective formation of asymmetric disulfides is preserved as monitored via 1H NMR experiments. Consequently, this new polypeptide overcomes the chain length limitations of poly(S-ethylsulfonyl-l-cysteine)s and thus provides convenient access to reactive poly(S-ethylsulfonyl-l-homocysteine)s for chemoselective disulfide formation.
