7MGQ

AICAR transformylase/IMP cyclohydrolase (ATIC) is essential for de novo purine biosynthesis and infection by Cryptococcus neoformans

7MGQ の概要

• エントリーDOI: 10.2210/pdb7mgq/pdb
• 分子名称: 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase, MAGNESIUM ION (3 entities in total)
• 機能のキーワード: isomerase, ligand, complex, structural protein
• 由来する生物種: Cryptococcus neoformans
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 262032.13

構造登録者

Wizrah, M.S.,Chua, S.M.H.,Luo, Z.,Manik, M.K.,Pan, M.,Whyte, J.M.,Robertson, A.B.,Kappler, U.,Kobe, B.,Fraser, J.A. (登録日: 2021-04-13, 公開日: 2022-04-20, 最終更新日: 2023-10-18)

主引用文献

Wizrah, M.S.I.,Chua, S.M.H.,Luo, Z.,Manik, M.K.,Pan, M.,Whyte, J.M.L.,Robertson, A.A.B.,Kappler, U.,Kobe, B.,Fraser, J.A.
AICAR transformylase/IMP cyclohydrolase (ATIC) is essential for de novo purine biosynthesis and infection by Cryptococcus neoformans.
J.Biol.Chem., 298:102453-102453, 2022

PubMed Abstract: The fungal pathogen Cryptococcus neoformans is a leading cause of meningoencephalitis in the immunocompromised. As current antifungal treatments are toxic to the host, costly, limited in their efficacy, and associated with drug resistance, there is an urgent need to identify vulnerabilities in fungal physiology to accelerate antifungal discovery efforts. Rational drug design was pioneered in de novo purine biosynthesis as the end products of the pathway, ATP and GTP, are essential for replication, transcription, and energy metabolism, and the same rationale applies when considering the pathway as an antifungal target. Here, we describe the identification and characterization of C. neoformans 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/5'-inosine monophosphate cyclohydrolase (ATIC), a bifunctional enzyme that catalyzes the final two enzymatic steps in the formation of the first purine base inosine monophosphate. We demonstrate that mutants lacking the ATIC-encoding ADE16 gene are adenine and histidine auxotrophs that are unable to establish an infection in a murine model of virulence. In addition, our assays employing recombinantly expressed and purified C. neoformans ATIC enzyme revealed K values for its substrates AICAR and 5-formyl-AICAR are 8-fold and 20-fold higher, respectively, than in the human ortholog. Subsequently, we performed crystallographic studies that enabled the determination of the first fungal ATIC protein structure, revealing a key serine-to-tyrosine substitution in the active site, which has the potential to assist the design of fungus-specific inhibitors. Overall, our results validate ATIC as a promising antifungal drug target.

PubMed: 36063996
DOI: 10.1016/j.jbc.2022.102453

実験手法

X-RAY DIFFRACTION (2.67 Å)