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01 January 2008

Use of di- and tripropionate substrate analogs to probe the active site of human recombinant coproporphyrinogen oxidase

Justin B. MorgenthalerABDE, Reyna L. BartoAB, Timothy D. LashADEF, Marjorie A. JonesADEFG

Med Sci Monit 2008; 14(1): BR1-7 :: ID: 636046

Abstract

Background
Defects in the enzyme coproporphyrinogen oxidase result in accumulation of porphyrins which may affect the severity of a subset of porphyrias. Thus evaluation of this enzyme for substrate selectivity is of value. Kinetic evaluations of recombinant human coproporphyrinogen oxidase have been undertaken using six di- and tripropionate analogs of the natural substrate coproporphyrinogen-III. These substrate analogs were modified by having alkyl groups in place of one or both of the ring 13- or 17-propionate moieties.
Material and Method
Cloned human enzyme was incubated with analogs under apparent first order conditions and with various substrate concentrations. The kinetic values, K(m) and V(max), were determined.
Results
Relative to the authentic substrate, the K(m) values for the 13-ethyl, dimethyl and diethyl porphyrinogens were very comparable whereas the K(m) values were much higher using dipropyl and dibutyl porphyrinogen and much lower for the 17-ethyl analog. For the dipropionate analogs, the V(max) values were an apparent function of the carbon length of the substituent on the C and D rings, with longer carbon length severely reducing product formation by some 4-5 orders of magnitude. Also, the two isomeric tripropionates that were tested indicated that it was more detrimental to have an ethyl group at the 13-position for both binding and catalysis.
Conclusions
This work extends our understanding of porphyrin ring substituent effects reported by Cooper et al. (2005). The substituents on both the C and D rings have significant effects on both the substrate binding and catalysis by this important enzyme.

Keywords: Recombinant Proteins - metabolism, Propionates - metabolism, Porphyrins - metabolism, Molecular Structure, Kinetics, Substrate Specificity, Coproporphyrinogen Oxidase - metabolism, Catalytic Domain

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