title: Substrates and Inhibitors of SAMHD1.
abstract: SAMHD1 hydrolyzes 2'-deoxynucleoside-5'-triphosphates (dNTPs) into 2'-deoxynucleosides and inorganic triphosphate products. In this paper, we evaluated the impact of 2' sugar moiety substitution for different nucleotides on being substrates for SAMHD1 and mechanisms of actions for the results. We found that dNTPs ((2'R)-2'-H) are only permissive in the catalytic site of SAMHD1 due to L150 exclusion of (2'R)-2'-F and (2'R)-2'-OH nucleotides. However, arabinose ((2'S)-2'-OH) nucleoside-5'-triphosphates analogs are permissive to bind in the catalytic site and be hydrolyzed by SAMHD1. Moreover, when the (2'S)-2' sugar moiety is increased to a (2'S)-2'-methyl as with the SMDU-TP analog, we detect inhibition of SAMHD1's dNTPase activity. Our computational modeling suggests that (2'S)-2'-methyl sugar moiety clashing with the Y374 of SAMHD1. We speculate that SMDU-TP mechanism of action requires that the analog first docks in the catalytic pocket of SAMHD1 but prevents the A351-V378 helix conformational change from being completed, which is needed before hydrolysis can occur. Collectively we have identified stereoselective 2' substitutions that reveal nucleotide substrate specificity for SAMHD1, and a novel inhibitory mechanism for the dNTPase activity of SAMHD1. Importantly, our data is beneficial for understanding if FDA-approved antiviral and anticancer nucleosides are hydrolyzed by SAMHD1 in vivo.
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hollenbaugh
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Jadd
authors.initials: J
authors.lastname: Shelton
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Sijia
authors.initials: S
authors.lastname: Tao
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Sheida
authors.initials: S
authors.lastname: Amiralaei
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lu
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Goetze
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Longhu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Informatics and Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: Nettles
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia United States of America.|Children's Healthcare of Atlanta, Atlanta, Georgia United States of America.|College of Pharmacy, Kyung-Hee University, Seoul, South Korea.
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
mesh_terms: D000818:Animals; D001085:Arabinofuranosylcytosine Triphosphate; D002241:Carbohydrates / Q000737:chemistry; D002645:Chickens; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009000:Monocytes / Q000166:cytology; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D000076106:SAM Domain and HD Domain-Containing Protein 1; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D002241:Carbohydrates; D004791:Enzyme Inhibitors; D009711:Nucleotides; D001085:Arabinofuranosylcytosine Triphosphate; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins