Human riboflavin kinase: Species‐specific traits in the biosynthesis of the FMN cofactor. Issue 8 (10th July 2020)

• Record Type: Journal Article
• Authors: Anoz‐Carbonell, Ernesto; Rivero, Maribel; Polo, Victor; Velázquez‐Campoy, Adrián; Medina, Milagros
• Is Part Of: FASEB journal. Volume 34:Issue 8(2020)
• Page Start: 10871
• Page End: 10886
• Publication Date: 2020-07-10
• Subjects: calorimetry -- kinetics limiting step -- ligand binding and cooperativity -- pre‐steady‐state kinetics -- product inhibition -- riboflavin kinase -- therapeutic target; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202000566R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Human riboflavin kinase ( Hs RFK) catalyzes vitamin B2 (riboflavin) phosphorylation to flavin mononucleotide (FMN), obligatory step in flavin cofactor synthesis. Hs RFK 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 Hs RFK activity, showing that both reaction products regulate it through competitive inhibition. Fast‐kinetic studies show that despite Hs RFK 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 Hs RFK availability, and envisage that interaction with its client‐apoproteins might favor FMN release. Finally, Hs RFK parameters differ from those of the so far evaluated bacterial counterparts, reinforcing the idea of species‐specific mechanisms in RFK catalysis. These observations support Hs RFK as potential therapeutic target because of its key functions, while also envisage bacterial RFK modules as potential antimicrobial targets.