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),Biochemistry

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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)
Biochemistry ( IF 2.9 ) Pub Date : 2020-11-02 , DOI: 10.1021/acs.biochem.0c00724
Xinyue Liu ₁ , Abigail Garber ₂ , Julia Ryan ₂ , Aditi Deshpande ₃ , Dagmar Ringe _{1,

3,

4} , Thomas C Pochapsky _{1,

3,

4}

Affiliation

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, converting 1,2-dihydroxy-5-(methylthio)pent-1-en-3-one (acireductone) into 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-methylthiopropionate, 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 the structures of 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. Nuclear magnetic resonance 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.

中文翻译：

人 Fe(II) 结合乙酰双加氧酶的溶液结构模型及其与基质金属蛋白酶 I (MMP-I) 调节域的相互作用

金属酶乙酰还原酮双加氧酶 (ARD) 显示金属依赖性物理和酶活性，具体取决于活性位点中结合的金属。 Fe(II) 结合酶催化蛋氨酸回收途径的倒数第二步，将 1,2-二羟基-5-(甲硫基)pent-1-en-3-one（乙酰还原酮）转化为甲酸盐和蛋氨酸的酮酸前体，2-酮基-4-硫代甲基-2-氧代丁酸酯，使用O ₂作为氧化剂。如果 Ni(II) 被结合，就会发生旁路分流，从相同的乙酰还原酮底物中产生 3-甲硫基丙酸盐、甲酸盐和一氧化碳。描述了 Fe(II) 结合的人类酶 HsARD 的溶液结构，并将其与密切相关的小鼠酶 MmARD 的 Ni 结合形式的结构进行了比较。讨论了两种异构体不同反应性的潜在原理。已发现人类酶通过结合 MMP-I 的细胞质跨膜尾肽来调节参与肿瘤转移的基质金属蛋白酶 I (MMP-I) 的活性。用 MMP-1 尾肽对 HsARD 进行核磁共振滴定可以鉴定 HsARD 上的肽结合位点，即与动态富含脯氨酸环相邻的金属结合位点前面的裂口。

更新日期：2020-11-12

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