Kinetic and structural analysis of human ALDH9A1

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F19%3A73597229" target="_blank" >RIV/61989592:15310/19:73597229 - isvavai.cz</a>

Výsledek na webu

<a href="https://portlandpress.com/bioscirep/article/doi/10.1042/BSR20190558/110870/Kinetic-and-structural-analysis-of-human-ALDH9A1" target="_blank" >https://portlandpress.com/bioscirep/article/doi/10.1042/BSR20190558/110870/Kinetic-and-structural-analysis-of-human-ALDH9A1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1042/BSR20190558" target="_blank" >10.1042/BSR20190558</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Kinetic and structural analysis of human ALDH9A1

Popis výsledku v původním jazyce

Aldehyde dehydrogenases (ALDHs) constitute a superfamily of NAD(P)(+)-dependent enzymes, which detoxify aldehydes produced in various metabolic pathways to the corresponding carboxylic acids. Among the 19 human ALDHs, the cytosolic ALDH9A1 has so far never been fully enzymatically characterized and its structure is still unknown. Here, we report complete molecular and kinetic properties of human ALDH9A1 as well as three crystal forms at 2.3, 2.9, and 2.5 angstrom resolution. We show that ALDH9A1 exhibits wide substrate specificity to aminoaldehydes, aliphatic and aromatic aldehydes with a clear preference for gamma-trimethylaminobutyraldehyde (TMABAL). The structure of ALDH9A1 reveals that the enzyme assembles as a tetramer. Each ALDH monomer displays a typical ALDHs fold composed of an oligomerization domain, a coenzyme domain, a catalytic domain, and an inter-domain linker highly conserved in amino-acid sequence and folding. Nonetheless, structural comparison reveals a position and a fold of the inter-domain linker of ALDH9A1 never observed in any other ALDH so far. This unique difference is not compatible with the presence of a bound substrate and a large conformational rearrangement of the linker up to 30 angstrom has to occur to allow the access of the substrate channel. Moreover, the alpha beta E region consisting of an alpha-helix and a beta-strand of the coenzyme domain at the dimer interface are disordered, likely due to the loss of interactions with the inter-domain linker, which leads to incomplete beta-nicotinamide adenine dinucleotide (NAD(+)) binding pocket.

Název v anglickém jazyce

Kinetic and structural analysis of human ALDH9A1

Popis výsledku anglicky

Aldehyde dehydrogenases (ALDHs) constitute a superfamily of NAD(P)(+)-dependent enzymes, which detoxify aldehydes produced in various metabolic pathways to the corresponding carboxylic acids. Among the 19 human ALDHs, the cytosolic ALDH9A1 has so far never been fully enzymatically characterized and its structure is still unknown. Here, we report complete molecular and kinetic properties of human ALDH9A1 as well as three crystal forms at 2.3, 2.9, and 2.5 angstrom resolution. We show that ALDH9A1 exhibits wide substrate specificity to aminoaldehydes, aliphatic and aromatic aldehydes with a clear preference for gamma-trimethylaminobutyraldehyde (TMABAL). The structure of ALDH9A1 reveals that the enzyme assembles as a tetramer. Each ALDH monomer displays a typical ALDHs fold composed of an oligomerization domain, a coenzyme domain, a catalytic domain, and an inter-domain linker highly conserved in amino-acid sequence and folding. Nonetheless, structural comparison reveals a position and a fold of the inter-domain linker of ALDH9A1 never observed in any other ALDH so far. This unique difference is not compatible with the presence of a bound substrate and a large conformational rearrangement of the linker up to 30 angstrom has to occur to allow the access of the substrate channel. Moreover, the alpha beta E region consisting of an alpha-helix and a beta-strand of the coenzyme domain at the dimer interface are disordered, likely due to the loss of interactions with the inter-domain linker, which leads to incomplete beta-nicotinamide adenine dinucleotide (NAD(+)) binding pocket.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

BIOSCIENCE REPORTS

ISSN

0144-8463

e-ISSN

—

Svazek periodika

39

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

"20190558-1"-"20190558-12"

Kód UT WoS článku

000466609400079

EID výsledku v databázi Scopus

2-s2.0-85065347069