PDBsum entry 1ef3

Oxidoreductase

PDB id: 1ef3

Contents

Protein chain

315 a.a. *

Ligands

NAP ×2

FID ×2

Waters ×25

* Residue conservation analysis

PDB id:

1ef3

Name:

Oxidoreductase

Title:

Fidarestat bound to human aldose reductase

Structure:

Aldose reductase. Chain: a, b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: muscle. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469

Resolution:

2.80Å R-factor: 0.186 R-free: 0.278

Authors:

M.Oka,Y.Matsumoto,S.Sugiyama,N.Tsuruta,M.Matsushima

Key ref:

M.Oka et al. (2000). A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2', 5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Fidarestat): its absolute configuration and interactions with the aldose reductase by X-ray crystallography. J Med Chem, 43, 2479-2483. PubMed id: 10882376 DOI: 10.1021/jm990502r

Date:

06-Feb-00 Release date: 07-Feb-01

Protein chains

P15121  (ALDR_HUMAN) -  Aldo-keto reductase family 1 member B1 from Homo sapiens

Seq: 316 a.a.

Struc: 315 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.1.1.21 - aldose reductase.
• Reaction:
  1. an alditol + NAD⁺ = an aldose + NADH + H⁺
  2. an alditol + NADP⁺ = an aldose + NADPH + H⁺

alditol + NAD(+) (Bound ligand (Het Group name = NAP) matches with 91.67% similarity) = aldose + NADH + H(+)

alditol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = aldose + NADPH + H(+)

• Enzyme class 2: E.C.1.1.1.300 - NADP-retinol dehydrogenase.
• Reaction: all-trans-retinol + NADP⁺ = all-trans-retinal + NADPH + H⁺

all-trans-retinol (Bound ligand (Het Group name = FID) matches with 41.38% similarity) + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = all-trans-retinal + NADPH + H(+)

• Enzyme class 3: E.C.1.1.1.372 - D/L-glyceraldehyde reductase.
• Reaction:
  1. glycerol + NADP⁺ = L-glyceraldehyde + NADPH + H⁺
  2. glycerol + NADP⁺ = D-glyceraldehyde + NADPH + H⁺

glycerol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = L-glyceraldehyde + NADPH + H(+)

glycerol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = D-glyceraldehyde + NADPH + H(+)

• Enzyme class 4: E.C.1.1.1.54 - allyl-alcohol dehydrogenase.
• Reaction: allyl alcohol + NADP⁺ = acrolein + NADPH + H⁺

allyl alcohol + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = acrolein + NADPH + 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/jm990502r

J Med Chem 43:2479-2483 (2000)

PubMed id: 10882376

A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2', 5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Fidarestat): its absolute configuration and interactions with the aldose reductase by X-ray crystallography.

M.Oka, Y.Matsumoto, S.Sugiyama, N.Tsuruta, M.Matsushima.

ABSTRACT

The absolute configuration of the aldose reductase (AR) inhibitor, (+)-(2S,4S)-6-fluoro-2',5'-dioxospiro¿chroman-4, 4'-imidazolidine-2-carboxamide (fidarestat), was established indirectly by single-crystal X-ray analysis of (+)-(2S, 4S)-8-bromo-6-fluoro-2',5'-dioxospiro¿chroman-4, 4'-imidazolidine-2-carboxylic acid (1). The crystal structure of human AR complexed with fidarestat was determined, and the specific inhibition activity was discussed on the basis of the three-dimensional interactions between them. The structure clarified that fidarestat was located in the active site by hydrophilic and hydrophobic interactions and that the carbamoyl group of fidarestat was a very effective substituent for affinity to AR and for selectivity between AR and aldehyde reductase (AHR). Explanations for the differences between the observed activities of fidarestat and its stereoisomer 2 were suggested by computer modeling.