Abstract
Aldehyde dehydrogenases engage in many cellular functions, however their dysfunction resulting in accumulation of their substrates can be cytotoxic. ALDHs are responsible for the NAD(P)-dependent oxidation of aldehydes to carboxylic acids, participating in detoxification, biosynthesis, antioxidant and regulatory functions. Severe diseases, including alcohol intolerance, cancer, cardiovascular and neurological diseases, were linked to dysfunctional ALDH enzymes, relating back to key enzyme structure. An in-depth understanding of the ALDH structure-function relationship and mechanism of action is key to the understanding of associated diseases. Principal structural features 1) cofactor binding domain, 2) active site and 3) oligomerization mechanism proved critical in maintaining ALDH normal activity. Emerging research based on the combination of structural, functional and biophysical studies of bacterial and eukaryotic ALDHs contributed to the appreciation of diversity within the superfamily. Herewith, we discuss these studies and provide our interpretation for a global understanding of ALDH structure and its purpose–including correct function and role in disease. Our analysis provides a synopsis of a common structure-function relationship to bridge the gap between the highly studied human ALDHs and lesser so prokaryotic models.
Highlights
Aldehyde dehydrogenases (ALDH) (EC 1.2.1.3) are a family of nicotinamide adenine dinucleotide (NAD(P)) dependent enzymes, typically with a molecular mass of ca. 50–60 kDa
Human ALDH1A1, ALDH2, ALDH3A1, and ALDH4A1 can carry out esterase activity Sládek (2003), with ALDH2
The ongoing ALDH structure-function investigation is important for elucidating the novel features of these enzymes as well as the underlying mechanism for the cause of many diseases
Summary
Aldehyde dehydrogenases (ALDH) (EC 1.2.1.3) are a family of nicotinamide adenine dinucleotide (phosphate) (NAD(P)) dependent enzymes, typically with a molecular mass of ca. 50–60 kDa. Aldehyde dehydrogenases (ALDH) (EC 1.2.1.3) are a family of nicotinamide adenine dinucleotide (phosphate) (NAD(P)) dependent enzymes, typically with a molecular mass of ca. 50–60 kDa. Aldehyde dehydrogenases (ALDH) (EC 1.2.1.3) are a family of nicotinamide adenine dinucleotide (phosphate) (NAD(P)) dependent enzymes, typically with a molecular mass of ca. They oxidise a large range of aliphatic and aromatic, endogenous and exogenous aldehydes to form the corresponding carboxylic acids They differ in their subcellular location, tissue distribution and preferred substrates while contributing to a broad spectrum of associated biological activities across prokaryotes, eukaryotes and Archaea. To date 10 out of the 19 human ALDHs have a resolved structure This led to misconceptions and a rather inaccurate description of typical features related to the enzyme family (Rodríguez-Zavala et al, 2006; Hayes et al, 2018). A recent study on the Pseudomonas genus identified 42 different classes of ALDHs demonstrating the scope of this enzyme’s diversity, but housed in a general, common structure (Riveros-Rosas et al, 2019)
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