Human riboflavin kinase: Species-specific traits in the biosynthesis of the FMN cofactor

Anoz-Carbonell, Ernesto (Universidad de Zaragoza) ; Rivero, Maribel ; Polo, Victor (Universidad de Zaragoza) ; Velázquez-Campoy, Adrián (Universidad de Zaragoza) ; Medina, Milagros (Universidad de Zaragoza)

Resumen: Human riboflavin kinase (HsRFK) catalyzes vitamin B2 (riboflavin) phosphorylation to flavin mononucleotide (FMN), obligatory step in flavin cofactor synthesis. HsRFK expression is related to protection from oxidative stress, amyloid-β toxicity, and some malignant cancers progression. Its downregulation alters expression profiles of clock-controlled metabolic-genes and destroys flavins protection on stroke treatments, while its activity reduction links to protein-energy malnutrition and thyroid hormones decrease. We explored specific features of the mechanisms underlying the regulation of HsRFK activity, showing that both reaction products regulate it through competitive inhibition. Fast-kinetic studies show that despite HsRFK binds faster and preferably the reaction substrates, the complex holding both products is kinetically most stable. An intricate ligand binding landscape with all combinations of substrates/products competing with the catalytic complex and exhibiting moderate cooperativity is also presented. These data might contribute to better understanding the molecular bases of pathologies coursing with aberrant HsRFK availability, and envisage that interaction with its client-apoproteins might favor FMN release. Finally, HsRFK parameters differ from those of the so far evaluated bacterial counterparts, reinforcing the idea of species-specific mechanisms in RFK catalysis. These observations support HsRFK as potential therapeutic target because of its key functions, while also envisage bacterial RFK modules as potential antimicrobial targets.

Idioma: Inglés

DOI: 10.1096/fj.202000566r

Año: 2020

Publicado en: The FASEB Journal 34, 8 (2020), 10871-10886
ISSN: 0892-6638

Factor impacto JCR: 5.191 (2020)

Categ. JCR: BIOLOGY rank: 14 / 93 = 0.151 (2020) - Q1 - T1
Categ. JCR: CELL BIOLOGY rank: 77 / 195 = 0.395 (2020) - Q2 - T2
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 84 / 297 = 0.283 (2020) - Q2 - T1

Factor impacto SCIMAGO: 1.709 - Biochemistry (Q1) - Biotechnology (Q1) - Molecular Biology (Q1) - Medicine (miscellaneous) (Q1) - Genetics (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA-FEDER/E35-20R
Financiación: info:eu-repo/grantAgreement/ES/MICINN-AEI/PID2019-103901GB-I00
Financiación: info:eu-repo/grantAgreement/ES/MINECO-AEI-FEDER/BIO2016-75183-P

Tipo y forma: Article (Published version)

Área (Departamento): Área Química Física (Dpto. Química Física)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)