A Model for the Solution Structure of Human Fe(II)-Bound Acireductone Dioxygenase and Interactions with the Regulatory Domain of Matrix Metalloproteinase I (MMP-I).
A Model for the Solution Structure of Human Fe(II)-Bound Acireductone Dioxygenase and Interactions with the Regulatory Domain of Matrix Metalloproteinase I (MMP-I).
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DOI：
10.1021/acs.biochem.0c00724
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发表时间：
2020-11-10
期刊：
影响因子：
2.9
通讯作者：
Pochapsky TC
中科院分区：
文献类型：
--
作者：
Liu X;Garber A;Ryan J;Deshpande A;Ringe D;Pochapsky TC
金属酶酸还原酮双加氧酶（ARD）显示金属依赖性的物理和酶活性取决于金属结合在活性位点。Fe（II）结合酶催化甲硫氨酸补救途径（MSP）的倒数第二步，使用O2作为氧化剂，将1，2-二羟基-5-（甲硫基）戊-1-烯-3-酮（酸还原酮）转化为甲酸盐和甲硫氨酸的酮酸前体2-酮-4-硫代甲基-2-氧代丁酸盐。如果Ni（II）被结合，则发生旁路分流，从相同的acreductone底物产生3-甲基硫代丙酸酯、甲酸酯和一氧化碳。的Fe（II）结合的人类酶，HsARD的溶液结构，描述和比较镍结合形式的密切相关的小鼠酶，MmARD。两种亚型的不同反应性的潜在理由进行了讨论。已发现人酶通过结合基质金属蛋白酶I（MMP-1）的胞质跨膜尾肽来调节MMP-1的活性，MMP-1参与肿瘤转移。用MMP-1尾肽对HsARD进行NMR滴定，可以鉴定HsARD上的肽结合位点，即与动态富含脯氨酸的环相邻的金属结合位点前的裂缝。
The metalloenzyme acireductone dioxygenase (ARD) shows metal-dependent physical and enzymatic activities depending upon the metal bound in the active site. The Fe(II)-bound enzyme catalyzes the penultimate step of the methionine salvage pathway (MSP), converting 1,2-dihydroxy-5-(methylthio)pent-1-en-3-one (acireductone) to formate and the ketoacid precursor of methionine, 2-keto-4-thiomethyl-2-oxobutanoate, using O2 as the oxidant. If Ni(II) is bound, an off-pathway shunt occurs, producing 3-methytthiopropionate, formate and carbon monoxide from the same acireductone substrate. The solution structure of the Fe(II)-bound human enzyme, HsARD, is described and compared with Ni-bound forms of the closely related mouse enzyme, MmARD. Potential rationales for the different reactivities of the two isoforms are discussed. The human enzyme has been found to regulate the activity of matrix metalloproteinase I (MMP-I), which is involved in tumor metastasis, by binding the cytoplasmic transmembrane tail peptide of MMP-I. NMR titration of HsARD with the MMP-I tail peptide permits identification of the peptide binding site on HsARD, a cleft anterior to the metal binding site adjacent to a dynamic proline-rich loop.
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