Structurally Linked Dynamics in Lactate Dehydrogenases of Evolutionarily Distinct Species.
Biochemistry
; 56(19): 2488-2496, 2017 05 16.
Article
em En
| MEDLINE
| ID: mdl-28445027
ABSTRACT
We present new findings about how primary and secondary structure affects the role of fast protein motions in the reaction coordinates of enzymatic reactions. Using transition path sampling and committor distribution analysis, we examined the difference in the role of these fast protein motions in the reaction coordinate of lactate dehydrogenases (LDHs) of Apicomplexa organisms Plasmodium falciparum and Cryptosporidium parvum. Having evolved separately from a common malate dehydrogenase ancestor, the two enzymes exhibit several important structural differences, notably a five-amino acid insertion in the active site loop of P. falciparum LDH. We find that these active site differences between the two organisms' LDHs likely cause a decrease in the contribution of the previously determined LDH rate-promoting vibration to the reaction coordinate of P. falciparum LDH compared to that of C. parvum LDH, specifically in the coupling of the rate-promoting vibration and the hydride transfer. This effect, while subtle, directly shows how changes in structure near the active site of LDH alter catalytically important motions. Insights provided by studying these alterations would prove to be useful in identifying LDH inhibitors that specifically target the isozymes of these parasitic organisms.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Modelos Moleculares
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Proteínas de Protozoários
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Cryptosporidium parvum
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Lactato Desidrogenases
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos