AMP binding sites are commonly used by nature for allosteric regulation of enzymes controlling the production and metabolism of carbohydrates and lipids. Since many of these enzymes represent potential drug targets for metabolic diseases, efforts were initiated to discover AMP mimics that bind to AMP-binding sites with high affinity and high enzyme specificity. Herein we report the structure-guided design of potent fructose 1,6-bisphosphatase (FBPase) inhibitors that interact with the AMP binding site on FBPase despite their structural dissimilarity to AMP. Molecular modeling, free-energy perturbation calculations, X-ray crystallography, and enzyme kinetic data guided our redesign of AMP, which began by replacing the 5'-phosphate with a phosphonic acid attached to C8 of the adenine base via a 3-atom spacer. Additional binding affinity was gained by replacing the ribose with an alkyl group that formed van der Waals interactions with a hydrophobic region within the AMP binding site and by replacing the purine nitrogens N1 and N3 with carbons to minimize desolvation energy expenditures. The resulting benzimidazole phosphonic acid, 16, inhibited human FBPase (IC50 = 90 nM) 11-fold more potently than AMP and exhibited high specificity for the AMP binding site on FBPase. 16 also inhibited FBPase in primary rat hepatocytes and correspondingly resulted in concentration-dependent inhibition of the gluconeogenesis pathway. Accordingly, these results suggest that the AMP site of FBPase may represent a potential drug target for reducing the excessive glucose produced by the gluconeogenesis pathway in patients with type 2 diabetes.

01 Nov 1982·Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology

Kinetic studies on asparagine synthetase from mung beans (Vigna radiata (L) wilczek) with a phosphonate analogue of a proposed reaction intermadiate

Author: Leonard Beevers ; David C. Pike

The aspartyl adenylate (I) analog, L-2-amino-4-oxo-5-(5'-adenosyl)phosphonopentanoic acid (II) was synthesized.I is proposed to occur during activities of asparagine synthetase (EC 6.3.5.4).Enzyme kinetic studies indicate that inhibition of the mung bean enzyme by II is noncompetitive with respect to glutamine and uncompetitive with respect to both ATP and aspartate, with a K_i of 0.08 mM.This suggests that if II is acting as an analog of I then the synthesis of asparagine involves the binding of I to 2 distinct sites on the enzyme.

01 Oct 1979·Archives of Biochemistry and BiophysicsQ3 · BIOLOGY

The synthesis and properties in enzymic reactions of substrate analogs containing the methylphosphonyl group

Q3 · BIOLOGY

Article

Author: Robert A. Lazarus ; Patricia A. Benkovic ; Stephen J. Benkovic

The properties of the methylphosphonyl group as a substrate analog for the phosphoryl moiety of various biol. phosphoryl donors was investigated in several enzymic phosphoryl transfer reactions.The synthesis and characterization of adenosine 5'-(β-methylphosphonyl)diphosphate, adenosine 5'-methylphosphonate, acetyl methylphosphonate, and methylphosphonoenolpyruvate are fully described.Adenosine 5'-(β-methylphosphonyl)diphosphate is not a substrate for adenylate kinase, hexokinase, 3-phosphoglycerate kinase, glycerol kinase, phosphofructokinase, creatine kinase, alk. phosphatase, or nucleoside 5'-diphosphophate kinase.Competitive inhibition of ATP was observed with hexokinase and 3-phosphoglycerate kinase with K_i/K_m ≃10.Adenosine 5'-methylphosphonate was a substrate for adenylate deaminase and 5'-nucleotidase, but not for adenylate kinase, acid phosphatase, 5'-phosphodiesterase, or 3'-phosphodiesterase.Acetyl methylphosphonate inhibits the reaction of acetyl phosphate with acetate kinase, but methylphosphonoenolpyruvate has no effect upon the reaction of phosphoenolpyruvate with pyruvate kinase.The results indicate that with the exception of 5'-nucleotidase, the methylphosphonyl group is incapable of undergoing transfer.One interpretation among others is that a metaphosphate-type mechanism is required for these processes.

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