PDBsum entry 4x4l

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4x4l

Contents

Protein chain

493 a.a.

Ligands

3XG

NAI

Metals

_NA

_YB ×2

_CL ×4

Waters ×184

PDB id:

4x4l

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Structure of human aldh1a1 with inhibitor cm037

Structure:

Retinal dehydrogenase 1. Chain: a. Synonym: raldh1,aldh-e1,alhdii,aldehyde dehydrogenase family 1 member a1,aldehyde dehydrogenase,cytosolic. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: aldh1a1, aldc, aldh1, pumb1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.85Å R-factor: 0.204 R-free: 0.233

Authors:

C.A.Morgan,T.D.Hurley

Key ref:

C.A.Morgan and T.D.Hurley (2015). Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1A1 inhibitors. J Med Chem, 58, 1964-1975. PubMed id: 25634381 DOI: 10.1021/jm501900s

Date:

03-Dec-14 Release date: 11-Feb-15

Protein chain

P00352  (AL1A1_HUMAN) -  Aldehyde dehydrogenase 1A1 from Homo sapiens

Seq: 501 a.a.

Struc: 493 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: E.C.1.2.1.19 - aminobutyraldehyde dehydrogenase.
• Reaction: 4-aminobutanal + NAD⁺ + H2O = 4-aminobutanoate + NADH + 2 H⁺

4-aminobutanal + NAD(+) + H2O (Bound ligand (Het Group name = NAI) corresponds exactly) = 4-aminobutanoate + NADH + 2 × H(+)

• Enzyme class 2: E.C.1.2.1.28 - benzaldehyde dehydrogenase (NAD(+)).
• Reaction: benzaldehyde + NAD⁺ + H2O = benzoate + NADH + 2 H⁺

benzaldehyde + NAD(+) + H2O (Bound ligand (Het Group name = NAI) corresponds exactly) = benzoate + NADH + 2 × H(+)

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

aldehyde + NAD(+) + H2O (Bound ligand (Het Group name = NAI) corresponds exactly) = carboxylate + NADH + 2 × H(+)

• Enzyme class 4: E.C.1.2.1.36 - retinal dehydrogenase.
• Reaction: retinal + NAD⁺ + H2O = retinoate + NADH + 2 H⁺

retinal + NAD(+) (Bound ligand (Het Group name = NAI) corresponds exactly) + H2O = retinoate + NADH + 2 × H(+)

• Cofactor: FAD

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/jm501900s

J Med Chem 58:1964-1975 (2015)

PubMed id: 25634381

Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1A1 inhibitors.

C.A.Morgan, T.D.Hurley.

ABSTRACT

Aldehyde dehydrogenases (ALDH) catalyze the irreversible oxidation of aldehydes to their corresponding carboxylic acid. Alterations in ALDH1A1 activity are associated with such diverse diseases as cancer, Parkinson's disease, obesity, and cataracts. Inhibitors of ALDH1A1 could aid in illuminating the role of this enzyme in disease processes. However, there are no commercially available selective inhibitors for ALDH1A1. Here we characterize two distinct chemical classes of inhibitors that are selective for human ALDH1A1 compared to eight other ALDH isoenzymes. The prototypical members of each structural class, CM026 and CM037, exhibit submicromolar inhibition constants but have different mechanisms of inhibition. The crystal structures of these compounds bound to ALDH1A1 demonstrate that they bind within the aldehyde binding pocket of ALDH1A1 and exploit the presence of a unique glycine residue to achieve their selectivity. These two novel and selective ALDH1A1 inhibitors may serve as chemical tools to better understand the contributions of ALDH1A1 to normal biology and to disease states.