Binding profile of quinonoid-dihydrobiopterin to quinonoid-dihydropteridine reductase examined by in silico and in vitro analyses.
J Biochem
; 174(5): 441-450, 2023 Oct 31.
Article
em En
| MEDLINE
| ID: mdl-37540845
Quinonoid dihydropteridine reductase (QDPR) catalyses the reduction of quinonoid-form dihydrobiopterin (qBH2) to tetrahydrobiopterin (BH4). BH4 metabolism is a drug target for neglected tropical disorders because trypanosomatid protozoans, including Leishmania and Trypanosoma, require exogenous sources of biopterin for growth. Although QDPR is a key enzyme for maintaining intracellular BH4 levels, the precise catalytic properties and reaction mechanisms of QDPR are poorly understood due to the instability of quinonoid-form substrates. In this study, we analysed the binding profile of qBH2 to human QDPR in combination with in silico and in vitro methods. First, we performed docking simulation of qBH2 to QDPR to obtain possible binding modes of qBH2 at the active site of QDPR. Then, among them, we determined the most plausible binding mode using molecular dynamics simulations revealing its atomic-level interactions and confirmed it with the in vitro assay of mutant enzymes. Moreover, it was found that not only qBH2 but also quinonoid-form dihydrofolate (qDHF) could be potential physiological substrates for QDPR, suggesting that QDPR may be a bifunctional enzyme. These findings in this study provide important insights into biopterin and folate metabolism and would be useful for developing drugs for neglected tropical diseases.
Palavras-chave
molecular dynamics; pteridine reductase; quinonoid-dihydropteridine reductase; tetrahydrobiopterinAbbreviations: AAAH, aromatic aminoacid hydroxylase; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; DHFR, dihydrofolate reductase; NADH, nicotinamide adenine dinucleotide; NAM, nicotinamide; MD, molecular dynamics; PT, pterin; PTR1, pteridine reductase 1; qBH2; quinonoid dihydrobiopterin; qDHF, quinonoid dihydrofolate; QDPR, quinonoid dihydropteridine reductase; SDR, short-chain dehydrogenase/reductase; THF, tetrahydrofolate
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biopterinas
/
Di-Hidropteridina Redutase
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article