Ligand binding phenomena that pertain to the metabolic function of renalase

Abstract

Renalase catalyzes the oxidation of isomers of β-NAD(P)H that carry the hydride in the 2 or 6 positions of the nicotinamide base to form β-NAD(P)+. This activity is thought to alleviate inhibition of multiple β-NAD(P)-dependent enzymes of primary and secondary metabolism by these isomers. Here we present evidence for a variety of ligand binding phenomena relevant to the function of renalase. We offer evidence of the potential for primary metabolism inhibition with structures of malate dehydrogenase and lactate dehydrogenase bound to the 6-dihydroNAD isomer. The previously observed preference of renalase from Pseudomonas for NAD-derived substrates over those derived from NADP is accounted for by the structure of the enzyme in complex with NADPH. We also show that nicotinamide nucleosides and mononucloetides reduced in the 2- and 6-positions are renalase substrates, but bind weakly. A seven-fold enhancement of acquisition (kred/Kd) for 6-dihydronicotinamide riboside was observed for human renalase in the presence of ADP. However, generally the addition of complement ligands, ADP for mononucloetide or AMP for nucleoside substrates, did not enhance the reductive half-reaction. Non-substrate nicotinamide nucleosides or nucleotides bind weakly suggesting that only β-NADH and β-NADPH compete with dinucleotide substrates for access to the active site.

Predicting protein–ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A

“…As such, inhibitors of this enzyme have been sought as potential therapeutics. Several classes of inhibitors of LDHA have been described and a wealth of structural information and binding affinity data are available 62–77. The set of compounds ( 1–11 ) studied include seven from high-throughput screening (HTS) of the Genentech/Roche corporate compound collection;66,68,69,71,72,78 two small, negatively charged compounds;73 and three compounds sharing malonate as a common substructure originating from AstraZeneca's fragment screening approach (Table 2, Fig.…”

Renalase—A new understanding of its enzymatic and non‐enzymatic activity and its implications for future research

“…Among all potentially applicable records only 43 focused on the subject by title and abstract. These papers were screened and divided into three areas: renalase enzymatic activity (16 records), 1,2,4,5,6,7,8,9,10,11,12,13,14,15,16,17 renalase polymorphisms (16 records) [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] and renalase non-enzymatic activity (11 records). [34][35][36][37][38][39][40][41][42][43][44]…”

Designing the Optimal Formulation for Biopharmaceuticals: A New Approach Combining Molecular Dynamics and Experiments

“…The rabbit muscle L-lactate dehydrogenase topology file was obtained from the RCSB Protein Data Bank (PDB 5KKC 27 ).…”