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在裂殖酵母中功能性表达所有人类磺基转移酶，建立方法学并构建同工酶 SULT4A1 和 SULT6B1 的结构模型。

Functional Expression of All Human Sulfotransferases in Fission Yeast, Assay Development, and Structural Models for Isoforms SULT4A1 and SULT6B1.

机构信息

School of Pharmaceutical Science and Technology, Health Sciences Platform, Tianjin University, Tianjin 300072, China.

Pharmaceutical and Medicinal Chemistry (Pharmaceutical Analyses), Institute of Pharmacy, Freie Universitaet Berlin, 14195 Berlin, Germany.

出版信息

Biomolecules. 2020 Nov 6;10(11):1517. doi: 10.3390/biom10111517.

DOI:10.3390/biom10111517
PMID:33171978
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7694633/
Abstract

Cytosolic sulfotransferases (SULTs) catalyze phase II (conjugation) reactions of drugs and endogenous compounds. A complete set of recombinant fission yeast strains each expressing one of the 14 human SULTs was generated, including SULT4A1 and SULT6B1. Sulfation of test substrates by whole-cell biotransformation was successfully demonstrated for all enzymes for which substrates were previously known. The results proved that the intracellular production of the cofactor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) necessary for SULT activity in fission yeast is sufficiently high to support metabolite production. A modified variant of sulfotransferase assay was also developed that employs permeabilized fission yeast cells (enzyme bags). Using this approach, SULT4A1-dependent sulfation of 1-naphthol was observed. Additionally, a new and convenient SULT activity assay is presented. It is based on the sulfation of a proluciferin compound, which was catalyzed by SULT1E1, SULT2A1, SULT4A1, and SULT6B1. For the latter two enzymes this study represents the first demonstration of their enzymatic functionality. Furthermore, the first catalytically competent homology models for SULT4A1 and SULT6B1 in complex with PAPS are reported. Through mechanistic molecular modeling driven by substrate docking, we pinned down the increased activity levels of these two isoforms to optimized substrate binding.

摘要

细胞质硫转移酶（SULTs）催化药物和内源性化合物的 II 相（结合）反应。生成了一组完整的重组裂殖酵母菌株，每个菌株表达 14 个人类 SULTs 之一，包括 SULT4A1 和 SULT6B1。对于先前已知底物的所有酶，通过全细胞生物转化成功证明了测试底物的硫酸化。结果证明，裂殖酵母中 SULT 活性所需的辅助因子 3'-磷酸腺苷 5'-磷酸硫酸酯（PAPS）的细胞内产生足够高，足以支持代谢产物的产生。还开发了一种改良的硫转移酶测定法，该方法采用通透性裂殖酵母细胞（酶袋）。使用这种方法，观察到 SULT4A1 依赖性 1-萘酚的硫酸化。此外，还提出了一种新的简便的 SULT 活性测定法。它基于前荧光素化合物的硫酸化，该化合物由 SULT1E1、SULT2A1、SULT4A1 和 SULT6B1 催化。对于后两种酶，本研究首次证明了它们的酶功能。此外，还报告了 SULT4A1 和 SULT6B1 与 PAPS 复合物的第一个催化功能同源模型。通过基于底物对接的机制分子建模，我们确定了这两个同工酶的活性水平提高是由于优化了底物结合。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/cb3b5321c2cd/biomolecules-10-01517-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/a2a51dbf807e/biomolecules-10-01517-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/d264229a1938/biomolecules-10-01517-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/755af8ab2fea/biomolecules-10-01517-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/7e5ccf7f43b9/biomolecules-10-01517-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/337b8f68716c/biomolecules-10-01517-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/bf8f6781851c/biomolecules-10-01517-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/4912c1185781/biomolecules-10-01517-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/cb3b5321c2cd/biomolecules-10-01517-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/a2a51dbf807e/biomolecules-10-01517-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/d264229a1938/biomolecules-10-01517-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/755af8ab2fea/biomolecules-10-01517-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/7e5ccf7f43b9/biomolecules-10-01517-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/337b8f68716c/biomolecules-10-01517-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/bf8f6781851c/biomolecules-10-01517-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/4912c1185781/biomolecules-10-01517-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1955/7694633/cb3b5321c2cd/biomolecules-10-01517-g008.jpg

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