Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase.
2-methylcitrate synthase
Aspergillus
coenzyme A
cooperativity
human citrate synthase
structure
Journal
Biological chemistry
ISSN: 1437-4315
Titre abrégé: Biol Chem
Pays: Germany
ID NLM: 9700112
Informations de publication
Date de publication:
26 11 2019
26 11 2019
Historique:
received:
09
01
2019
accepted:
15
05
2019
pubmed:
30
5
2019
medline:
14
4
2020
entrez:
30
5
2019
Statut:
ppublish
Résumé
Aspergillus fumigatus is a ubiquitous fungus that is not only a problem in agriculture, but also in healthcare. Aspergillus fumigatus drug resistance is becoming more prominent which is mainly attributed to the widespread use of fungicides in agriculture. The fungi-specific 2-methylcitrate cycle is responsible for detoxifying propionyl-CoA, a toxic metabolite produced as the fungus breaks down proteins and amino acids. The enzyme responsible for this detoxification is 2-methylcitrate synthase (mcsA) and is a potential candidate for the design of new anti-fungals. However, mcsA is very similar in structure to human citrate synthase (hCS) and catalyzes the same reaction. Therefore, both enzymes were studied in parallel to provide foundations for design of mcsA-specific inhibitors. The first crystal structures of citrate synthase from humans and 2-methylcitrate synthase from A. fumigatus are reported. The determined structures capture various conformational states of the enzymes and several inhibitors were identified and characterized. Despite a significant homology, mcsA and hCS display pronounced differences in substrate specificity and cooperativity. Considering that the active sites of the enzymes are almost identical, the differences in reactions catalyzed by enzymes are caused by residues that are in the vicinity of the active site and influence conformational changes of the enzymes.
Identifiants
pubmed: 31141475
doi: 10.1515/hsz-2019-0106
pii: hsz-2019-0106
doi:
Substances chimiques
Citrate (si)-Synthase
EC 2.3.3.1
2-methylcitrate synthase
EC 2.3.3.5
Oxo-Acid-Lyases
EC 4.1.3.-
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1567-1581Références
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