Human glutathione-dependent formaldehyde dehydrogenase. Structural changes associated with ternary complex formation

Paresh C. Sanghani, William F. Bosron, Thomas Hurley

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Human glutathione-dependent formaldehyde dehydrogenase plays an important role in the metabolism of glutathione adducts such as S-(hydroxymethyl)glutathione and S-nitrosoglutathione. The role of specific active site residues in binding these physiologically important substrates and the structural changes during the catalytic cycle of glutathione-dependent formaldehyde dehydrogenase was examined by determining the crystal structure of a ternary complex with S-(hydroxymethyl)glutathione and the reduced coenzyme to 2.6 Å resolution. The formation of the ternary complex caused the movement of the catalytic domain toward the coenzyme-binding domain. This represents the first observation of domain closure in glutathione-dependent formaldehyde dehydrogenase in response to substrate binding. A water molecule adjacent to the 2′-ribose hydroxyl of NADH suggests that the alcohol proton is relayed to solvent directly from the coenzyme, rather than through the action of the terminal histidine residue as observed in the proton relay system for class I alcohol dehydrogenases. S-(Hydroxymethyl)glutathione is directly coordinated to the active site zinc and forms interactions with the highly conserved residues Arg114, Asp55, Glu57, and Thr46. The active site zinc has a tetrahedral coordination environment with Cys44, His66, and Cys173 as the three protein ligands in addition to S-(hydroxymethyl)glutathione. This is in contrast to zinc coordination in the binary coenzyme complex where all of the ligands were contributed by the enzyme and included Glu67 as the fourth protein ligand. This change in zinc coordination is accomplished by an ∼2.3 Å movement of the catalytic zinc.

Original languageEnglish
Pages (from-to)15189-15194
Number of pages6
JournalBiochemistry
Volume41
Issue number51
DOIs
StatePublished - Dec 24 2002

Fingerprint

glutathione-independent formaldehyde dehydrogenase
Coenzymes
Glutathione
Zinc
Catalytic Domain
Ligands
Protons
S-Nitrosoglutathione
Ribose
Alcohol Dehydrogenase
Histidine
Hydroxyl Radical
NAD
Proteins
Alcohols
Observation
formaldehyde dehydrogenase (glutathione)
Substrates
Metabolism
Water

ASJC Scopus subject areas

  • Biochemistry

Cite this

Human glutathione-dependent formaldehyde dehydrogenase. Structural changes associated with ternary complex formation. / Sanghani, Paresh C.; Bosron, William F.; Hurley, Thomas.

In: Biochemistry, Vol. 41, No. 51, 24.12.2002, p. 15189-15194.

Research output: Contribution to journalArticle

@article{a2d1a640b29549a1ad746b9c4c6f4ea9,
title = "Human glutathione-dependent formaldehyde dehydrogenase. Structural changes associated with ternary complex formation",
abstract = "Human glutathione-dependent formaldehyde dehydrogenase plays an important role in the metabolism of glutathione adducts such as S-(hydroxymethyl)glutathione and S-nitrosoglutathione. The role of specific active site residues in binding these physiologically important substrates and the structural changes during the catalytic cycle of glutathione-dependent formaldehyde dehydrogenase was examined by determining the crystal structure of a ternary complex with S-(hydroxymethyl)glutathione and the reduced coenzyme to 2.6 {\AA} resolution. The formation of the ternary complex caused the movement of the catalytic domain toward the coenzyme-binding domain. This represents the first observation of domain closure in glutathione-dependent formaldehyde dehydrogenase in response to substrate binding. A water molecule adjacent to the 2′-ribose hydroxyl of NADH suggests that the alcohol proton is relayed to solvent directly from the coenzyme, rather than through the action of the terminal histidine residue as observed in the proton relay system for class I alcohol dehydrogenases. S-(Hydroxymethyl)glutathione is directly coordinated to the active site zinc and forms interactions with the highly conserved residues Arg114, Asp55, Glu57, and Thr46. The active site zinc has a tetrahedral coordination environment with Cys44, His66, and Cys173 as the three protein ligands in addition to S-(hydroxymethyl)glutathione. This is in contrast to zinc coordination in the binary coenzyme complex where all of the ligands were contributed by the enzyme and included Glu67 as the fourth protein ligand. This change in zinc coordination is accomplished by an ∼2.3 {\AA} movement of the catalytic zinc.",
author = "Sanghani, {Paresh C.} and Bosron, {William F.} and Thomas Hurley",
year = "2002",
month = "12",
day = "24",
doi = "10.1021/bi026705q",
language = "English",
volume = "41",
pages = "15189--15194",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "51",

}

TY - JOUR

T1 - Human glutathione-dependent formaldehyde dehydrogenase. Structural changes associated with ternary complex formation

AU - Sanghani, Paresh C.

AU - Bosron, William F.

AU - Hurley, Thomas

PY - 2002/12/24

Y1 - 2002/12/24

N2 - Human glutathione-dependent formaldehyde dehydrogenase plays an important role in the metabolism of glutathione adducts such as S-(hydroxymethyl)glutathione and S-nitrosoglutathione. The role of specific active site residues in binding these physiologically important substrates and the structural changes during the catalytic cycle of glutathione-dependent formaldehyde dehydrogenase was examined by determining the crystal structure of a ternary complex with S-(hydroxymethyl)glutathione and the reduced coenzyme to 2.6 Å resolution. The formation of the ternary complex caused the movement of the catalytic domain toward the coenzyme-binding domain. This represents the first observation of domain closure in glutathione-dependent formaldehyde dehydrogenase in response to substrate binding. A water molecule adjacent to the 2′-ribose hydroxyl of NADH suggests that the alcohol proton is relayed to solvent directly from the coenzyme, rather than through the action of the terminal histidine residue as observed in the proton relay system for class I alcohol dehydrogenases. S-(Hydroxymethyl)glutathione is directly coordinated to the active site zinc and forms interactions with the highly conserved residues Arg114, Asp55, Glu57, and Thr46. The active site zinc has a tetrahedral coordination environment with Cys44, His66, and Cys173 as the three protein ligands in addition to S-(hydroxymethyl)glutathione. This is in contrast to zinc coordination in the binary coenzyme complex where all of the ligands were contributed by the enzyme and included Glu67 as the fourth protein ligand. This change in zinc coordination is accomplished by an ∼2.3 Å movement of the catalytic zinc.

AB - Human glutathione-dependent formaldehyde dehydrogenase plays an important role in the metabolism of glutathione adducts such as S-(hydroxymethyl)glutathione and S-nitrosoglutathione. The role of specific active site residues in binding these physiologically important substrates and the structural changes during the catalytic cycle of glutathione-dependent formaldehyde dehydrogenase was examined by determining the crystal structure of a ternary complex with S-(hydroxymethyl)glutathione and the reduced coenzyme to 2.6 Å resolution. The formation of the ternary complex caused the movement of the catalytic domain toward the coenzyme-binding domain. This represents the first observation of domain closure in glutathione-dependent formaldehyde dehydrogenase in response to substrate binding. A water molecule adjacent to the 2′-ribose hydroxyl of NADH suggests that the alcohol proton is relayed to solvent directly from the coenzyme, rather than through the action of the terminal histidine residue as observed in the proton relay system for class I alcohol dehydrogenases. S-(Hydroxymethyl)glutathione is directly coordinated to the active site zinc and forms interactions with the highly conserved residues Arg114, Asp55, Glu57, and Thr46. The active site zinc has a tetrahedral coordination environment with Cys44, His66, and Cys173 as the three protein ligands in addition to S-(hydroxymethyl)glutathione. This is in contrast to zinc coordination in the binary coenzyme complex where all of the ligands were contributed by the enzyme and included Glu67 as the fourth protein ligand. This change in zinc coordination is accomplished by an ∼2.3 Å movement of the catalytic zinc.

UR - http://www.scopus.com/inward/record.url?scp=0037168478&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037168478&partnerID=8YFLogxK

U2 - 10.1021/bi026705q

DO - 10.1021/bi026705q

M3 - Article

C2 - 12484756

AN - SCOPUS:0037168478

VL - 41

SP - 15189

EP - 15194

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 51

ER -