Effects of Clinical Mutations in the Second Coordination Sphere and Remote Regions on the Catalytic Mechanism of Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Aspartyl Hydroxylase AspH

Author:

Krishnan Anandhu1ORCID,Waheed Sodiq O.1ORCID,Melayikandy Sreerag1,LaRouche Ciara2,Paik Meredith1,Schofield Christopher J.3ORCID,Karabencheva‐Christova Tatyana G.1ORCID

Affiliation:

1. Department of Chemistry Michigan Technological University Houghton MI-49931 USA

2. Department of Chemical Engineering, Michigan Techno Department of Chemistry Michigan Technological University Houghton MI-49931 USA

3. Chemistry Research Laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford Oxford OX1 3TA United Kingdom

Abstract

AbstractAspartyl/asparaginyl hydroxylase (AspH) catalyzes the post‐translational hydroxylations of vital human proteins, playing an essential role in maintaining their biological functions. Single‐point mutations in the Second Coordination Sphere (SCS) and long‐range (LR) residues of AspH have been linked to pathological conditions such as the ophthalmologic condition Traboulsi syndrome and chronic kidney disease (CKD). Although the clinical impacts of these mutations are established, there is a critical knowledge gap regarding their specific atomistic effects on the catalytic mechanism of AspH. In this study, we report integrated computational investigations on the potential mechanistic implications of four mutant forms of human AspH with clinical importance: R735W, R735Q, R688Q, and G434V. All the mutant forms exhibited altered binding interactions with the co‐substrate 2‐oxoglutarate (2OG) and the main substrate in the ferric‐superoxo and ferryl complexes, which are critical for catalysis, compared to the wild‐type (WT). Importantly, the mutations strongly influence the energetics of the frontier molecular orbitals (FMOs) and, thereby, the activation energies for the hydrogen atom transfer (HAT) step compared to the WT AspH. Insights from our study can contribute to enzyme engineering and the development of selective modulators for WT and mutants of AspH, ultimately aiding in treating cancers, Traboulsi syndrome and, CKD.

Funder

National Institutes of Health

Cancer Research UK

Publisher

Wiley

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3