Human arginase II: crystal structure and physiological role in male and female sexual arousal

Biochemistry. 2003 Jul 22;42(28):8445-51. doi: 10.1021/bi034340j.

Abstract

Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. The X-ray crystal structure of a fully active, truncated form of human arginase II complexed with a boronic acid transition state analogue inhibitor has been determined at 2.7 A resolution. This structure is consistent with the hydrolysis of l-arginine through a metal-activated hydroxide mechanism. Given that human arginase II appears to play a role in regulating l-arginine bioavailability to NO synthase in human penile corpus cavernosum smooth muscle, the inhibition of human arginase II is a potential new strategy for the treatment of erectile dysfunction [Kim, N. N., Cox, J. D., Baggio, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speicher, D. W., Morris, S. M., Ash, D. E., Traish, A. M., and Christianson, D. W. (2001) Biochemistry 40, 2678-2688]. Since NO synthase is found in human clitoral corpus cavernosum and vagina, we hypothesized that human arginase II is similarly present in these tissues and functions to regulate l-arginine bioavailability to NO synthase. Accordingly, hemodynamic studies conducted with a boronic acid arginase inhibitor in vivo are summarized, suggesting that the extrahepatic arginase plays a role in both male and female sexual arousal. Therefore, arginase II is a potential target for the treatment of male and female sexual arousal disorders.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arginase / antagonists & inhibitors
  • Arginase / chemistry*
  • Arginase / genetics
  • Arousal / physiology*
  • Base Sequence
  • Binding Sites
  • Crystallography, X-Ray / methods
  • DNA Primers
  • Enzyme Inhibitors / pharmacology
  • Female
  • Genetic Variation
  • Hemodynamics / physiology*
  • Humans
  • Isoenzymes
  • Male
  • Models, Molecular
  • Polymerase Chain Reaction
  • Protein Structure, Secondary
  • Rabbits
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Sequence Deletion
  • Sexuality / physiology*

Substances

  • DNA Primers
  • Enzyme Inhibitors
  • Isoenzymes
  • Recombinant Proteins
  • ARG2 protein, human
  • Arginase

Associated data

  • PDB/1PQ3