Alcohol oxidation is an indispensable chemical reaction in biological systems. This process, biologically catalyzed by alcohol dehydrogenases (ADHs) and alcohol oxidases (AOXs), follows two distinct chemical routes depending on the cofactor. ADHs have been widely demonstrated to require Zn2+- and NAD(P)+-based cosubstrates. Except for galactose oxidase, AOXs achieve their conversion of alcohols to aldehydes or ketones using flavin-based cofactors. The FMN-dependent α-hydroxy acid-oxidizing enzymes and the glucose–methanol–choline (GMC) superfamily abstract their substrate's α–OH proton using a catalytic histidine, leading to substrate oxidation and flavin reduction. However, there is no known alcohol oxidation mechanism for enzymes requiring both a flavin and a metal. The Pseudomonas aeruginosa d-2-hydroxyglutarate dehydrogenase (PaD2HGDH) is a recently characterized α-hydroxy acid dehydrogenase that converts d-2-hydroxyglutarate or d-malate to 2-ketoglutarate or oxaloacetate, respectively. PaD2HGDH requires FAD and Zn2+ for catalysis. Previous studies on PaD2HGDH have identified a highly conserved active site histidine residue whose position is topologically conserved for catalytic bases in FMN-dependent α-hydroxy acid-oxidizing enzymes and the GMC superfamily of oxidoreductases. In this study, solvent isotope effects (SIEs) coupled with pL-rate profiles and a viscosity control have been used to probe the role of the Zn2+ cofactor in the C2–OH oxidation of d-malate and flavin reduction of PaD2HGDH. The data revealed an inverse solvent equilibrium isotope effect (SEIE) of 0.51 ± 0.09 consistent with a Zn2+-triggered abstraction of the substrate C2–OH proton that initiates d-malate oxidation and flavin reduction. The system provides insights into the role of Zn2+ in the oxidation mechanism of PaD2HGDH and, by extension, metallo flavoprotein dehydrogenases.

Joanna Afokai Quaye

Giovanni Gadda

ACS Bio & Med Chem Au

ACS Bio &Med Chem Au是开放获取期刊，发表生物和药物化学各个方面的短文、综合文章、评论和观点。欢迎提供基本见解或描述新颖合成的研究，以及临床或其它基于应用的工作。期刊收稿范围包括对生命所有领域的生物或细胞功能的化学、物理、机械和/或结构基础的实验和理论研究。它涵盖了化学生物学、合成生物学、疾病生物学、细胞生物学、农业和食品、天然产物研究、核酸生物学、神经科学、结构生物学和生物物理学等领域。

期刊收录研究方向：
药物化学，包括化合物设计和优化，生物学评估，药物递送和药物递送系统的分子机理理解，成像剂以及小生物活性分子和大生物活性分子的药理学和转化科学
用于鉴定（或结构 - 活性关系分析）生物活性分子，配体及其靶标的新型计算，化学信息学和结构研究
应用已建立的计算方法的计算研究，但只能与新颖和原始的实验数据相结合（例如，在设计和测试新化合物的情况下）
与传染病相关的文章 病原体，宿主 - 病原体相互作用，治疗，诊断，疫苗，药物输送系统以及与传染病有关的其他生物医学技术开发
ACS Bio & Med Chem Au is a broad scope, open access journal, which publishes short letters, comprehensive articles, reviews, and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses, as well as clinical or other applications-based work, are welcomed.

This broad scope includes experimental and theoretical studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, agriculture and food, natural products research, nucleic acid biology, neuroscience, structural biology, and biophysics.

The journal publishes studies that pertain to a broad range of medicinal chemistry, including compound design and optimization, biological evaluation, molecular mechanistic understanding of drug delivery and drug delivery systems, imaging agents, and pharmacology and translational science of both small and large bioactive molecules. Novel computational, cheminformatics, and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules, ligands, and their targets, are also welcome. The journal will consider computational studies applying established computational methods, but only in combination with novel and original experimental data (e.g., in cases where new compounds have been designed and tested).

Also included in the scope of the journal are articles relating to infectious diseases research on pathogens, host-pathogen interactions, therapeutics, diagnostics, vaccines, drug-delivery systems, and other biomedical technology development pertaining to infectious diseases.

ACS Bio & Med Chem Au is an open access journal that covers all aspects of biological and medicinal chemistry, publishing short letters, comprehensive articles, reviews, and perspectives. We welcome studies that provide fundamental insights or describe novel syntheses, as well as clinical or other application-based work. The journal's scope includes experimental and theoretical studies on the chemical, physical, mechanistic, and/or structural basis of biological or cellular functions across all domains of life. It encompasses fields such as chemical biology, synthetic biology, disease biology, cell biology, agriculture and food, natural products research, nucleic acid biology, neuroscience, structural biology, and biophysics.\n\nThe journal focuses on research directions including: \n- Medicinal chemistry, encompassing compound design and optimization, biological evaluation, molecular mechanistic understanding of drug delivery and drug delivery systems, imaging agents, and the pharmacology and translational science of both small and large bioactive molecules. \n- Novel computational, cheminformatics, and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules, ligands, and their targets. \n- Computational studies applying established computational methods, but only in combination with novel and original experimental data (e.g., in cases where new compounds have been designed and tested). \n- Research related to infectious diseases, including pathogens, host-pathogen interactions, therapeutics, diagnostics, vaccines, drug delivery systems, and other biomedical technology development pertaining to infectious diseases.

ACS Bio & Med Chem Au 是一本开放获取的期刊，涵盖生物和药物化学的各个方面，发表短文、综合文章、评论和观点。我们欢迎提供基本见解或描述新颖合成的研究，以及临床或其他基于应用的工作。期刊的收稿范围包括对生命各领域生物或细胞功能的化学、物理、机械和/或结构基础的实验和理论研究。涉及的领域包括化学生物学、合成生物学、疾病生物学、细胞生物学、农业与食品、天然产物研究、核酸生物学、神经科学、结构生物学和生物物理学等。\n\n期刊关注的研究方向包括：\n- 药物化学，包括化合物设计与优化、生物学评估、药物递送及其系统的分子机理理解、成像剂，以及小型和大型生物活性分子的药理学与转化科学。\n- 新型计算、化学信息学和结构研究，用于鉴定（或结构-活性关系分析）生物活性分子、配体及其靶标。\n- 应用已建立的计算方法的计算研究，但需与新颖和原始的实验数据结合（例如，在设计和测试新化合物的情况下）。\n- 与传染病相关的研究，包括病原体、宿主-病原体相互作用、治疗、诊断、疫苗、药物递送系统以及与传染病相关的其他生物医学技术开发。

Metal-Triggered FAD Reduction in d-2-Hydroxyglutarate Dehydrogenase from Pseudomonas aeruginosa PAO1

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Journal Info

Category	Quartile
CHEMISTRY, MEDICINAL	2