MOLECULAR CHANGES IN PORPHOBILINOGEN DEAMINASE IN AIP

Shoolingin-Jordan P.1, McNeill L.2

 

1Division of Biochemistry and Molecular Biology, School of Biological Sciences, University of Southampton, 2Oxford Centre for Molecular Sciences, Oxford University, UK

 

 

Acute intermittent porphyria is essentially a hepatic disease in which porphobilinogen deaminase is approximately halved in heterozygote carriers.  This reduction in the level of porpobilinogen deaminase is also reflected in erythrocytes that also show approximately 50% of the normal value.  However, during an acute attack, levels of hepatic porphobilinogen deaminase are reduced to values as little as 25% causing a further drop in haem synthesis, whereas the erythrocyte enzyme level remains relatively unchanged. The structural basis for the lowered levels of hepatic porphobilinogen deaminase during the acute attack, noted by Marver in the 1970s, has been traced to the post-translational step involving the assembly of the dipyrromethane cofactor. This is achieved by the reaction of apo-porphobilinogen deaminase with the 1-hydroxymethylbilane, preuroporphyrinogen.  We have found that this process is strongly inhibited by porphobilinogen. During an acute attack, it is therefore likely that the level of porphobilinogen is sufficiently high to prevent the formation of active porphobilinogen deaminase holo-enzyme.  In hepatic tissue where there is a rapid turnover of porphobilinogen deaminase the effect is magnified compared with erythrocytes that have a half life of several weeks.