Mechanistic studies of two dioxygenases in the methionine salvage pathway of Klebsiella pneumoniae

Biochemistry. 2001 May 29;40(21):6379-87. doi: 10.1021/bi010110y.

Abstract

Two dioxygenases (ARD and ARD') were cloned from Klebsiella pneumoniae that catalyze different oxidative decomposition reactions of an advanced aci-reductone intermediate, CH(3)SCH(2)CH(2)COCH(OH)=CH(OH) (I), in the methionine salvage pathway. The two enzymes are remarkable in that they have the same polypeptide sequence but bind different metal ions (Ni(2+) and Fe(2+), respectively). ARD converts I to CH(3)SCH(2)CH(2)COOH, CO, and HCOOH. ARD' converts I to CH(3)SCH(2)CH(2)COCOOH and HCOOH. Kinetic analyses suggest that both ARD and ARD' have ordered sequential mechanisms. A model substrate (II), a dethio analogue of I, binds to the enzyme first as evidenced by its lambda(max) red shift upon binding. The dianion formation from II causes the same lambda(max) red shift, suggesting that II bind to the enzyme as a dianion. The electron-rich II dianion likely reacts with O(2) to form a peroxide anion intermediate. Previous (18)O(2) and (14)C tracer experiments established that ARD incorporates (18)O(2) into C(1) and C(3) of II and C(2) is released as CO. ARD' incorporates (18)O(2) into C(1) and C(2) of II. The product distribution seems to necessitate the formation of a five-membered cyclic peroxide intermediate for ARD and a four-membered cyclic peroxide intermediate for ARD'. A model chemical reaction demonstrates the chemical and kinetic competency of the proposed five-membered cyclic peroxide intermediate. The breakdown of the four-membered and five-membered cyclic peroxide intermediates gives the ARD' and ARD products, respectively. The nature of the metal ion appears to dictate the attack site of the peroxide anion and, consequently, the different cyclic peroxide intermediates and the different oxidative cleavages of II. A cyclopropyl substrate analogue inactivates both enzymes after multiple turnovers, providing evidence that a radical mechanism may be involved in the formation of the peroxide anion intermediate.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anions / metabolism
  • Catalysis
  • Cyclopropanes / metabolism
  • Deoxyadenosines / metabolism
  • Dioxygenases*
  • Electron Spin Resonance Spectroscopy
  • Escherichia coli / enzymology
  • Escherichia coli / genetics
  • Ferric Compounds / metabolism
  • Free Radicals / metabolism
  • Glyoxylates / metabolism
  • Hydrogen Peroxide / metabolism
  • Kinetics
  • Klebsiella pneumoniae / enzymology*
  • Klebsiella pneumoniae / genetics
  • Methionine / metabolism*
  • Models, Chemical
  • Nickel / metabolism
  • Oxidation-Reduction
  • Oxygenases / chemistry*
  • Oxygenases / genetics
  • Oxygenases / isolation & purification
  • Oxygenases / metabolism*
  • Spectrophotometry, Ultraviolet
  • Substrate Specificity
  • Thionucleosides / metabolism

Substances

  • Anions
  • Cyclopropanes
  • Deoxyadenosines
  • Ferric Compounds
  • Free Radicals
  • Glyoxylates
  • Thionucleosides
  • 5'-methylthioadenosine
  • Nickel
  • Methionine
  • Hydrogen Peroxide
  • Oxygenases
  • Dioxygenases
  • aci-reductone oxidase (CO-forming)
  • glyoxylic acid