New insights into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase.

Background: Aldehydes are highly reactive molecules. While several non-P450 enzyme systems participate in their metabolism, one of the most important is the aldehyde dehydrogenase (ALDH) superfamily, composed of NAD(P)+-dependent enzymes that catalyze aldehyde oxidation. Objective: This article presents a review of what is currently known about each member of the human ALDH superfamily including the pathophysiological significance of these enzymes. Methods: Relevant literature involving all members of the human ALDH family was extensively reviewed, with the primary focus on recent and novel findings. Conclusion: To date, 19 ALDH genes have been identified in the human genome and mutations in these genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases, including Sjogren-Larsson syndrome, type II hyperprolinemia, γ-hydroxybutyric aciduria and pyridoxine-dependent seizures. ALDH enzymes also play important roles in embryogenesis and development, neurotransmissi...

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Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.

Twelve aldehyde dehydrogenase (ALDH) genes have been identified in humans. These genes, located on different chromosomes, encode a group of enzymes which oxidizes varieties of aliphatic and aromatic aldehydes. Metabolic disorders and clinical problems associated with mutations of ALDH1, ALDH2, ALDH4, ALDH10 and succinic semialdehyde (SSDH) genes have been emerged. Comparison of the human ALDHs indicates a wide range of divergency (> 80−< 15 % identity at the protein sequence level) among them. However, several protein regions, some of which are implicated in functional activities, are conserved in the family members.



The phylogenic tree constructed of 56 ALDH sequences of humans, animals, fungi, protozoa and eubacteria, suggests that the present-day human ALDH genes were derived from four ancestral genes that existed prior to the divergence of Eubacteria and Eukaryotes. The neighbor-joining tree derived from 12 human ALDHs and antiquitin indicates that diversification within the ALDH1/2/5/6 gene cluster occurred during the Neoproterozoic period (about 800 million years ago). Duplication in the ALDH 3/10/7/8 gene cluster occurred in Phanerozoic period (about 300 million years ago). Separations of ALDH3/ALDH10 and that of ALDH7/ALDH8 had occurred during the period of appearance and radiation of mammalian species.

Human aldehyde dehydrogenase gene family

Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. ALDH2, as a key enzyme that oxidizes acetaldehyde, is crucial for alcohol metabolism. ALDH1A1 and ALDH3A1 are lens and corneal crystallins, which are essential elements of the cellular defense mechanism against ultraviolet radiation-induced damage in ocular tissues. Many ALDH isozymes are important in oxidizing reactive aldehydes derived from lipid peroxidation and thereby help maintain cellular homeostasis. Increased expression and activity of ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. As a direct consequence of their significant physiological and toxicological roles, inhibitors of the ALDH enzymes have been developed to treat human diseases. This review summarizes known ALDH inhibitors, their mechanisms of action, isozyme selectivity, potency, and clinical uses. The purpose of this review is to 1) establish the current status of pharmacological inhibition of the ALDHs, 2) provide a rationale for the continued development of ALDH isozyme-selective inhibitors, and 3) identify the challenges and potential therapeutic rewards associated with the creation of such agents.

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

Insect antifreeze proteins (AFP) are much more effective than fish AFPs at depressing solution freezing points by ice-growth inhibition1,2. AFP from the beetle Tenebrio molitor is a small protein (8.4 kDa) composed of tandem 12-residue repeats3 (TCTxSxxCxxAx). Here we report its 1.4-A resolution crystal structure, showing that this repetitive sequence translates into an exceptionally regular β-helix. Not only are the 12-amino-acid loops almost identical in the backbone, but also the conserved side chains are positioned in essentially identical orientations, making this AFP perhaps the most regular protein structure yet observed. The protein has almost no hydrophobic core but is stabilized by numerous disulphide and hydrogen bonds. On the conserved side of the protein, threonine-cysteine-threonine motifs are arrayed to form a flat β-sheet, the putative ice-binding surface. The threonine side chains have exactly the same rotameric conformation and the spacing between OH groups is a near-perfect match to the ice lattice. Together with tightly bound co-planar external water, three ranks of oxygen atoms form a two-dimensional array, mimicking an ice section.

Mimicry of ice structure by surface hydroxyls and water of a β-helix antifreeze protein

The first structure of an aldehyde dehydrogenase (ALDH) is described at 2.6 A resolution. Each subunit of the dimeric enzyme contains an NAD-binding domain, a catalytic domain and a bridging domain. At the interface of these domains is a 15 A long funnel-shaped passage with a 6 × 12 A opening leading to a putative catalytic pocket. A new mode of NAD binding, which differs substantially from the classic β-α-β binding mode associated with the ‘Rossmann fold’, is observed which we term the β-α,β mode. Sequence comparisons of the class 3 ALDH with other ALDHs indicate a similar polypeptide fold, novel NAD-binding mode and catalytic site for this family. A mechanism for enzymatic specificity and activity is postulated.

The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold.

The crystal structure of a dipeptide complex of bovine neurophysin II has been solved at 2.8 A resolution solely by using single-wavelength anomalous scattering data from a single iodinated derivative. The asymmetric unit is an elongated tetramer of dimensions 110 x 40 x 30 A, composed of two dimers related by pseudo twofold symmetry. Each monomer consists of two homologous layers, each with four antiparallel beta-strands. The two regions are connected by a helix followed by a long loop. Monomer-monomer contacts involve antiparallel beta-sheet interactions, which form a dimer with two layers of eight beta-strands. One peptide per monomer occupies the principal hormone-binding pocket formed by part of the amino-terminal region and parts of the connecting helix and loop, with binding to protein consistent with conclusions drawn from solution studies. Dimer-dimer contacts involve the Tyr49 region adjacent to this site. A fifth dipeptide, of unknown biological significance, helps to stabilize one of the monomer-monomer interfaces and the tetramer-tetramer network in the crystal.

Crystal structure of a bovine neurophysin II dipeptide complex at 2.8 A determined from the single-wavelength anomalous scattering signal of an incorporated iodine atom.

Class 3 ALDHs prefer NAD as coenzyme, but can use NADP effectively in vitro. They function as dimers of identical ~50kDa monomers, and share about 30% sequence identity with either of the tetrameric class 1 or 2 enzymes. Interest in the Class 3 ALDH (ALDH-3) has focused on its diversity of expression (Lindahl, 1992). No ALDH-3 activity is detectable in normal mammalian liver, but high levels are obtained after exposure to certain xenobiotics. Many neoplasms possess elevated ALDH-3 activities, while many normal tissues, such as cornea and stomach constitutively express ALDH-3. ALDH-3 enzymes prefer aromatic aldehydes and medium chain-length (C-6 to C-10) aliphatic aldehydes as substrate. Known substrates include benzaldehyde and hexenal as well as 4-hydroxynonenal derived from membrane lipid peroxidation (Lindahl and Peterson, 1991). The microsomal ALDH-3 has also received clinical attention from the recent demonstration that Sjogren-Larsson Syndrome is the result of mutations inactivating this “fatty aldehyde dehydrogenase” (DeLaurenzi, et al, 1996).

Crystal structure of a class 3 aldehyde dehydrogenase at 2.6 A resolution.

Ricin-OR, an antitumor toxin, has been crystallized in space group P2 with cell parameters a= 8.77 nm, b= 4.64 nm, c= 7.64 nm and β=101°. There is one molecule in the asymmetric unit and the solvent content is estimated to be 48% by volume. The crystals diffract to 0.25 nm resolution which is higher than that of the previously reported C2 crystal form which had a solvent content of 65%.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1989.tb14651.x

Wen-Rui Chang

Papers

The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold.

Crystal structure of a bovine neurophysin II dipeptide complex at 2.8 A determined from the single-wavelength anomalous scattering signal of an incorporated iodine atom.

Crystal structure of a class 3 aldehyde dehydrogenase at 2.6 A resolution.

A new crystal form of ricin-OR.