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22 December 2006

Investigation of the catalytic and structural roles of conserved histidines of human coproporphyrinogen oxidase using site-directed mutagenesis

Shani J. Gitter, Christopher L. Cooper, Jon A. Friesen, Timothy D. Lash, Marjorie A. Jones

Med Sci Monit 2007; 13(1): BR1-10 :: ID: 470138

Abstract

Background: The catalytic contribution of four conserved histidines of human coproporphyrinogen oxidase (CPO) has been investigated using site-directed mutagenesis to change histidine (H) into alanine (A).
Material/Methods: The wild-type and mutant enzyme forms were analyzed for their ability to utilize coproporphyrinogen- III, mesoporphyrinogen-VI, and harderoporphyrinogen as substrates.
Results: Wild-type CPO had specifi c activities of 4.9±0.9 nmole product/min/mg for coproporphyrinogen- III, 1.7±0.7 nmole product/min/mg for mesoporphyrinogen-VI, and 5.1±1.8 nmole product/ min/mg for harderoporphyrinogen. The four mutant enzymes were catalytically competent
with all three substrates, but to varying degrees. The most affected mutant was the H158A enzyme which exhibited approximately 50-fold lower activity than wild-type recombinant CPO.
Conclusions: Thus, His158 of human CPO may have a role in the active site, but none of the conserved histidine residues of human coproporphyrinogen oxidase is essential for catalytic activity although changes in histidines have been implicated in the disease state hereditary coproporphyria.

Keywords: Conserved Sequence, Catalysis, Amino Acid Sequence, Coproporphyrinogen Oxidase - metabolism, Coproporphyrinogens - chemistry, Escherichia coli, Histidine - metabolism, Kinetics, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutant Proteins - metabolism, Oligopeptides, Recombinant Proteins - metabolism, Structure-Activity Relationship

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750