title: Nucleotide promiscuity of 3-phosphoglycerate kinase is in focus: implications for the design of better anti-HIV analogues.
abstract: The wide specificity of 3-phosphoglycerate kinase (PGK) towards its nucleotide substrate is a property that allows contribution of this enzyme to the effective phosphorylation (i.e. activation) of nucleotide-based pro-drugs against HIV. Here, the structural basis of the nucleotide-PGK interaction is characterised in comparison to other kinases, namely pyruvate kinase (PK) and creatine kinase (CK), by enzyme kinetic analysis and structural modelling (docking) studies. The results provided evidence for favouring the purine vs. pyrimidine base containing nucleotides for PGK rather than for PK or CK. This is due to the exceptional ability of PGK in forming the hydrophobic contacts of the nucleotide rings that assures the appropriate positioning of the connected phosphate-chain for catalysis. As for the D-/L-configurations of the nucleotides, the L-forms (both purine and pyrimidine) are well accepted by PGK rather than either by PK or CK. Here again the dominance of the hydrophobic interactions of the L-form of pyrimidines with PGK is underlined in comparison with those of PK or CK. Furthermore, for the l-forms, the absence of the ribose OH-groups with PGK is better tolerated for the purine than for the pyrimidine containing compounds. On the other hand, the positioning of the phosphate-chain is an even more important term for PGK in the case of both purines and pyrimidines with an L-configuration, as deduced from the present kinetic studies with various nucleotide-site mutants of PGK. These characteristics of the kinase-nucleotide interactions can provide a guideline for designing new drugs.
authors.affiliation: Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, P O Box 7, H-1518 Budapest, Hungary. varga@enzim.hu vas@enzim.hu
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.forename: Laurent
authors.initials: L
authors.lastname: Chaloin
authors.forename: Gyula
authors.initials: G
authors.lastname: Sági
authors.forename: Róbert
authors.initials: R
authors.lastname: Sendula
authors.forename: Eva
authors.initials: E
authors.lastname: Gráczer
authors.forename: Károly
authors.initials: K
authors.lastname: Liliom
authors.forename: Péter
authors.initials: P
authors.lastname: Závodszky
authors.forename: Corinne
authors.initials: C
authors.lastname: Lionne
authors.forename: Mária
authors.initials: M
authors.lastname: Vas
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000737:chemistry*; D020134:Catalytic Domain; D003198:Computer Simulation; D003402:Creatine Kinase / Q000737:chemistry; D015195:Drug Design; D057075:Enzyme Assays; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D009701:Nucleoside-Diphosphate Kinase / Q000737:chemistry; D009711:Nucleotides / Q000737:chemistry*; D010735:Phosphoglycerate Kinase / Q000737:chemistry* / Q000235:genetics; D011355:Prodrugs / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011770:Pyruvate Kinase / Q000737:chemistry; D013379:Substrate Specificity
chemical_list: D019380:Anti-HIV Agents; D009711:Nucleotides; D011355:Prodrugs; D011770:Pyruvate Kinase; D010735:Phosphoglycerate Kinase; D003402:Creatine Kinase; D009701:Nucleoside-Diphosphate Kinase