PDBsum entry 4zvx

Oxidoreductase

PDB id: 4zvx

Contents

Protein chains

474 a.a.

Waters ×312

PDB id:

4zvx

Name:

Oxidoreductase

Title:

Structure of apo human aldh7a1 in space group p4212

Structure:

Alpha-aminoadipic semialdehyde dehydrogenase. Chain: a, b. Synonym: alpha-aasa dehydrogenase,aldehyde dehydrogenase family 7 member a1,antiquitin-1,betaine aldehyde dehydrogenase,delta1- piperideine-6-carboxylate dehydrogenase,p6c dehydrogenase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: aldh7a1, atq1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.90Å R-factor: 0.170 R-free: 0.195

Authors:

J.J.Tanner

Key ref:

M.Luo and J.J.Tanner (2015). Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1. Biochemistry, 54, 5513-5522. PubMed id: 26260980 DOI: 10.1021/acs.biochem.5b00754

Date:

18-May-15 Release date: 26-Aug-15

Protein chains

P49419  (AL7A1_HUMAN) -  Alpha-aminoadipic semialdehyde dehydrogenase from Homo sapiens

Seq: 539 a.a.

Struc: 474 a.a.

Enzyme reactions

• Enzyme class 2: E.C.1.2.1.3 - aldehyde dehydrogenase (NAD(+)).
• Reaction: an aldehyde + NAD⁺ + H2O = a carboxylate + NADH + 2 H⁺
• Enzyme class 3: E.C.1.2.1.31 - L-aminoadipate-semialdehyde dehydrogenase.

Pathway:

• Reaction:
  1. (S)-2-amino-6-oxohexanoate + NADP⁺ + H2O = L-2-aminoadipate + NADPH + 2 H⁺
  2. (S)-2-amino-6-oxohexanoate + NAD⁺ + H2O = L-2-aminoadipate + NADH + 2 H⁺
• Enzyme class 4: E.C.1.2.1.8 - betaine-aldehyde dehydrogenase.
• Reaction: betaine aldehyde + NAD⁺ + H2O = glycine betaine + NADH + 2 H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.biochem.5b00754

Biochemistry 54:5513-5522 (2015)

PubMed id: 26260980

Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1.

M.Luo, J.J.Tanner.

ABSTRACT

Aldehyde dehydrogenase 7A1 (ALDH7A1) is part of lysine catabolism and catalyzes the NAD(+)-dependent oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Herein, we describe a structural study of human ALDH7A1 focused on substrate recognition. Five crystal structures and small-angle X-ray scattering data are reported, including the first crystal structure of any ALDH7 family member complexed with α-aminoadipate. The product binds with the ε-carboxylate in the oxyanion hole, the aliphatic chain packed into an aromatic box, and the distal end of the product anchored by electrostatic interactions with five conserved residues. This binding mode resembles that of glutamate bound to the proline catabolic enzyme ALDH4A1. Analysis of ALDH7A1 and ALDH4A1 structures suggests key interactions that underlie substrate discrimination. Structures of apo ALDH7A1 reveal dramatic conformational differences from the product complex. Product binding is associated with a 16 Å movement of the C-terminus into the active site, which stabilizes the active conformation of the aldehyde substrate anchor loop. The fact that the C-terminus is part of the active site was hitherto unknown. Interestingly, the C-terminus and aldehyde anchor loop are disordered in a new tetragonal crystal form of the apoenzyme, implying that these parts of the enzyme are highly flexible. Our results suggest that the active site of ALDH7A1 is disassembled when the aldehyde site is vacant, and the C-terminus is a mobile element that forms quaternary structural interactions that aid aldehyde binding. These results are relevant to the c.1512delG genetic deletion associated with pyridoxine-dependent epilepsy, which alters the C-terminus of ALDH7A1.