The aldehyde dehydrogenase superfamilies: correlations and deviations in structure and function

Abstract

Aldehyde dehydrogenases participate in many biochemical pathways, either by degrading organic substrates via organic acids or by producing reactive aldehyde intermediates in many biosynthetic pathways, and are becoming increasingly important for constructing synthetic metabolic pathways. Although they consist of simple and highly conserved basic structural motifs, they exhibit a surprising variability in the reactions catalyzed. We attempt here to give an overview of the known enzymes of two superfamilies comprising the known aldehyde dehydrogenases, focusing on their structural similarities and the residues involved in the catalytic reactions. The analysis reveals that the enzymes of the two superfamilies share many common traits and probably have a common evolutionary origin. While all enzymes catalyzing irreversible aldehyde oxidation to acids exhibit a universally conserved reaction mechanism with shared catalytic active-site residues, the enzymes capable of reducing activated acids to aldehydes deviate from this mechanism, displaying different active-site modifications required to allow these reactions which apparently evolved independently in different enzyme subfamilies. KEY POINTS: • The two aldehyde dehydrogenase superfamilies share significant similarities. • Catalytic amino acids of irreversibly acting AlDH are universally conserved. • Reductive or reversible reactions are enabled by water exclusion via the loss of conserved residues.

Keywords: Aldehyde dehydrogenase; Catalytic mechanism; Conserved domains; Glyceraldehyde-3-phosphate; Structure–function relations.

Fig. 1

Domain organization of enzymes from some representative subclades of the AlDH or GapDH superfamilies. The conserved domains or subunits are represented by different shades of red to visualize their composition of different subdomains (magenta, NAD(P) binding; red, catalytic; pink, protein interaction), and the approximate location of important catalytic amino acids is shown. Amino acids in yellow or green represent deviations from the usually conserved active-site residues; X indicates exchange of conserved catalytic residues in an enzymatically inactive AlDH16 enzyme

Fig. 2

Exemplary structures of aldehyde substrates mentioned in this article

Fig. 3

Representative structures of AlDH subunits or domains in various AlDH superfamily members. AlDH1 from Homo sapiens (4WJ9), AlDH2 from Bos taurus (1A4Z), succinic semialdehyde dehydrogenase from Homo sapiens (2W8N), long chain aldehyde dehydrogenase from Mycobacterium tuberculosis (3B4W), methylmalonyl semialdehyde dehydrogenase from Bacillus subtilis (1T90), 3,4-dehydroadipyl-CoA semialdehyde dehydrogenase from Burkholderia xenovorans (2VRO), AlDH domain of the proline utilization protein from Bradyrhizobium diazoefficiens (3HAZ), γ-glutamyl-phosphate reductase from Burkholderia thailandensis (4GHK), AlDH domain of AlDH16 from Loktanella sp. (6MVR), fatty acid reductase LuxC from Photobacterium phosphoreum (7XC6), AlDH domain of 10-formyltetrahydrofolate dehydrogenase from Homo sapiens (7YJJ), and succinyl-CoA reductase from Clostridium kluyveri (8CEK)

Fig. 4

Representative structures of members of the GapDH superfamily. Aspartate semialdehyde dehydrogenase from Escherichia coli (1BRM), GapDH II from Methanothermus fervidus (1CF2), GapDH I from E. coli (1DC4), aldolase/aldehyde dehydrogenase from Pseudomonas sp. (1NVM), N-acetyl-γ-glutamyl-phosphate reductase from Mycobacterium tuberculosis (2I3A), archaeal malonyl-CoA reductase from Sulfurisphaera tokodaii (4DPL), LysY from Thermus thermophilus (5EIO), and carbonic acid reductase from Segniliparus rugosus (5MSV)

Fig. 5

Active site and reaction mechanism of AlDH1. Top: Structural view of the conserved catalytic residues of the active site of AlDH1 with bound NADH. The residues of the catalytic triad are shown together with Phe466 and the “neck” residue Val460 (semi-transparent), and distances between Cys303 and important surrounding groups are indicated in Å. Bottom: Proposed catalytic mechanism of AlDH1 and other aldehyde-oxidizing AlDHs

Fig. 6

Active-site geometries of various members of the GapDH superfamily. A GapDH I from E. coli, B AlDH from Pseudomonas sp., C ArgC from Mycobacterium tuberculosis, and D Asd from Haemophilus influenzae. The structures have been aligned to show the same spatial orientations within the active sites to highlight the highly divergent relative locations of the His residues repurposed for activating the active-site Cys in the different subtypes within the superfamily

Fig. 7

Proposed catalytic mechanism used by enzymes of the AAA reductase and CAR families. The substrate gets adenylated at the adenylation domain (A) from where it is transesterified to a phosphopantetheine (blue line) bound by the transfer domain (T). The covalently bound thioester is then transferred to the reductase domain (R) where the substrate is reduced and finally released. The adenylation activation (ADA) domain present in AAA reductases is not shown in this scheme

Fig. 8

Phylogenetic tree of the AlDH superfamily. AlDH subfamilies and cd categories of the subclades are indicated and can be referred to in the text. Note that the tree contains a few categories that are not mentioned in the review because of insufficient state of knowledge. The bacterial malonyl-CoA reductases (MCR) were used for rooting this tree as well as the one for the GapDH superfamily

Fig. 9

Phylogenetic tree of the GapDH superfamily. Subclade identifiers and cd numbers are indicated and can be referred to in the text. Note that the tree contains a few categories that are not mentioned in the review because of insufficient state of knowledge. Black branches refer to sequences without any conserved active-site residues and (probably) inactive as AlDH. The bacterial malonyl-CoA reductases (MCR) were used for rooting this tree as well as the one for the AlDH superfamily