Liver Transplantation in Acute Hepatic Porphyria and Erythropoietic Protoporphyria

Wåhlin, Staffan; Harper, Pauline

doi:10.1142/9789814407755_0033

Cited by 1 publication

(1 citation statement)

References 115 publications

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“…Salient clinical features of EPP patients include PPIX accumulation in erythroid cells in the bone marrow and painful photosensitivity (6,8). Elimination of the PPIX excess can also have taxing effects on the liver, causing liver damage and terminal failure in rare cases (9,10).…”

Section: Introductionmentioning

confidence: 99%

Ferrochelatase π-helix: Implications from examining the role of the conserved π-helix glutamates in porphyrin metalation and product release

Gillam

Hunter

Ferreira

2018

Archives of Biochemistry and Biophysics

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Protoporphyrin ferrochelatase catalyzes the insertion of Fe into protoporphyrin IX to form heme. To determine whether a conserved, active site π-helix contributes to the translocation of the metal ion substrate to the ferrochelatase-bound porphyrin substrate, the invariant π-helix glutamates were replaced with amino acids with non-negatively charged side chains, and the kinetic mechanisms of the generated variants were examined. Analysis of yeast wild-type ferrochelatase-, E314Q- and E318Q-catalyzed reactions, under multi- and single-turnover conditions, demonstrated that the mutations of the π-helix glutamates hindered both protoporphyrin metalation and release of the metalated porphyrin, by slowing each step by approximately 30-50%. Protoporphyrin metalation occurred with an apparent pK of 7.3 ± 0.1, which was assigned to binding of Fe by deprotonated Glu-314 and Glu-314-assisted Fe insertion into the porphyrin ring. We propose that unwinding of the π-helix concomitant with the adoption of a protein open conformation positions the deprotonated Glu-314 to bind Fe from the surface of the enzyme. Transition to the closed conformation, with π-helix winding, brings Glu-314-bound Fe to the active site for incorporation into protoporphyrin.

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