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首页> 外文期刊>Biochimica et biophysica acta: BBA: International journal of biochemistry, biophysics and molecular biololgy. Proteins and Proteomics >Fine tuning of the active site modulates specificity in the interaction of O-acetylserine sulfhydrylase isozymes with serine acetyltransferase
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Fine tuning of the active site modulates specificity in the interaction of O-acetylserine sulfhydrylase isozymes with serine acetyltransferase

机译：活性位点的微调可调节O-乙酰丝氨酸巯基化酶同工酶与丝氨酸乙酰转移酶相互作用的特异性

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摘要

O-acetylserine sulfhydrylase (OASS) catalyzes the synthesis of l-cysteine in the last step of the reductive sulfate assimilation pathway in microorganisms. Its activity is inhibited by the interaction with serine acetyltransferase (SAT), the preceding enzyme in the metabolic pathway. Inhibition is exerted by the insertion of SAT C-terminal peptide into the OASS active site. This action is effective only on the A isozyme, the prevalent form in enteric bacteria under aerobic conditions, but not on the B-isozyme, the form expressed under anaerobic conditions. We have investigated the active site determinants that modulate the interaction specificity by comparing the binding affinity of thirteen pentapeptides, derived from the C-terminal sequences of SAT of the closely related species Haemophilus influenzae and Salmonella typhimurium, towards the corresponding OASS-A, and towards S. typhimurium OASS-B. We have found that subtle changes in protein active sites have profound effects on protein-peptide recognition. Furthermore, affinity is strongly dependent on the pentapeptide sequence, signaling the relevance of P3-P4-P5 for the strength of binding, and P1-P2 mainly for specificity. The presence of an aromatic residue at P3 results in high affinity peptides with Kdiss in the micromolar and submicromolar range, regardless of the species. An acidic residue, like aspartate at P4, further strengthens the interaction and results in the higher affinity ligand of S. typhimurium OASS-A described to date. Since OASS knocked-out bacteria exhibit a significantly decreased fitness, this investigation provides key information for the development of selective OASS inhibitors, potentially useful as novel antibiotic agents. ? 2012 Elsevier B.V. All rights reserved.
机译：O-乙酰丝氨酸巯基化酶（OASS）在微生物中还原性硫酸盐同化途径的最后一步催化L-半胱氨酸的合成。它的活性被丝氨酸乙酰转移酶（SAT）（代谢途径中的前一种酶）的相互作用所抑制。通过将SAT C末端肽插入OASS活性位点来发挥抑制作用。该作用仅对需氧条件下肠细菌中普遍存在的A同工酶有效，而对厌氧条件下所表达的B同工酶则无效。我们已经研究了活性位点决定因素，其通过比较十三种五肽的亲和力来调节相互作用的特异性，所述五种五肽来自密切相关的流感嗜血杆菌和鼠伤寒沙门氏菌的SAT的C端序列，对相应的OASS-A和对鼠伤寒沙门氏菌OASS-B。我们发现蛋白质活性位点的细微变化对蛋白质-肽的识别具有深远的影响。此外，亲和力强烈依赖于五肽序列，表明P3-P4-P5与结合强度相关，而P1-P2主要与特异性相关。在P3处存在芳族残基会产生高亲和力的肽，其Kdiss在微摩尔和亚微摩尔范围内，无论其种类如何。酸性残基（如P4处的天冬氨酸）进一步增强了相互作用，并导致迄今为止描述的鼠伤寒沙门氏菌OASS-A的亲和力更高。由于OASS敲除细菌的适应性显着降低，因此本研究为开发选择性OASS抑制剂提供了重要信息，这些抑制剂有可能用作新型抗生素。 ？ 2012 Elsevier B.V.保留所有权利。

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