Disease relevance of Hmbs

• Acute intermittent porphyria (AIP) is a human disease resulting from a dominantly inherited partial deficiency of the heme biosynthetic enzyme, porphobilinogen deaminase (PBGD) [1].
• Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria [1].
• To study the pathogenesis of the neurologic symptoms of AIP we have generated Pbgd-deficient mice by gene targeting [1].
• Here we show that PBGD-/- mice develop impairment of motor coordination and muscle weakness [2].
• These findings resemble those found in studies of affected nerves of patients with acute porphyria and thus provide strong evidence that PBGD deficiency causes degeneration of motor axons without signs of primary demyelination, thereby resolving a long-standing controversy [2].
• PBGD deficiency in erythroid tissue is not associated with phenotypic manifestations of acute porphyria [3].

High impact information on Hmbs

• These mice exhibit the typical biochemical characteristics of human AIP, notably, decreased hepatic Pbgd activity, increased delta-aminolevulinic acid synthase activity and massively increased urinary excretion of the heme precursor, delta-aminolevulinic acid after treatment with drugs such as phenobarbital [1].
• Interestingly, the neuropathy in PBGD-/- mice developed chronically and progressively and in the presence of normal or only slightly (twofold) increased plasma and urinary levels of the putative neurotoxic heme precursor delta-aminolevulinic acid [2].
• Histologically femoral nerves of PBGD-/- mice exhibit a marked decrease in large-caliber (>8 microm) axons and ultrastructural changes consistent with primary motor axon degeneration, secondary Schwann cell reactions, and axonal regeneration [2].
• Characterization of hypersensitive sites, protein-binding motifs, and regulatory elements in both promoters of the mouse porphobilinogen deaminase gene [4].
• Accumulation of porphobilinogen deaminase, uroporphyrinogen decarboxylase, and alpha- and beta-globin mRNAs during differentiation of mouse erythroleukemic cells. Effects of succinylacetone [5].

Chemical compound and disease context of Hmbs

• PBGD-deficient mice (PBGD-/-) imitate acute porphyria through massive induction of hepatic delta-aminolevulinic acid synthase by drugs such as phenobarbital [2].

Biological context of Hmbs

• Limited heme synthesis in porphobilinogen deaminase-deficient mice impairs transcriptional activation of specific cytochrome P450 genes by phenobarbital [6].
• The Ups locus has been mapped to mouse chromosome 9 in a three-point cross [7].

Anatomical context of Hmbs

• Fluorescence immunostaining with anti-PBGD antibodies revealed a major PBGD fraction in the nucleus and a minor fraction in the cytosol [8].
• In the brain, CYP1A1 protein was detected not only at the endoplasmic reticulum (ER), but also in the cytosol of PBGD-/- mice [9].

Associations of Hmbs with chemical compounds

• We have monitored, during the dimethyl sulfoxide (Me2SO)-induced differentiation of MEL cells, the accumulation of mRNAs encoding two enzymes of the heme biosynthetic pathway, namely porphobilinogen deaminase and uroporphyrinogen decarboxylase [5].
• Concerning porphyrin biosynthesis, no effect was observed with catalase and superoxide dismutase whereas increases of 57 and 87% were obtained with glutathione and melatonin, respectively, indicating that these antioxidants may prevent the oxidation of porphobilinogen deaminase, reactivating so that the AIP genetically reduced enzyme [10].
• A marked decrease in total PBGD activity and PpIX synthesis was observed following stimulation by butyrate, while HMBA induced an opposite effect [8].
• Furthermore, 7-deethylation of ethoxyresorufin, an indicator of CYP1A1 metabolic activity, could be restored by heme in cytosol of PBGD-/- mouse brain [9].
• Tumor and liver were excised and 5-aminolevulinic acid dehydratase and porphobilinogen deaminase activities were determined [11].

Regulatory relationships of Hmbs

• The activity and mRNA level of this particular cytochrome P450 are significantly lower in the phenobarbital-induced porphobilinogen deaminase-deficient mice (55% and 43%, respectively), but its expression can be restored to normal values when exogenous heme is administered [6].

Other interactions of Hmbs

• Exceptions to the preferred association of alleles of Es-17 and Ups have been found in three feral populations and one inbred strain [12].
• Ups is unlinked to Lv, which encodes the previous enzyme in the heme biosynthesis pathway [7].
• Namely, mRNAs for the erythroid-specific ALAS, delta-aminolevulinate dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase started to increase at 12, 18, 18-24 and 24 h, respectively [13].

Analytical, diagnostic and therapeutic context of Hmbs

• The study demonstrates that hepatic PBGD expression prevents the accumulation of porphyrin precursors, suggesting a future potential for gene therapy in AIP [14].
• Differentiation-dependent photodynamic therapy regulated by porphobilinogen deaminase in B16 melanoma [8].
• When these vectors were used to deliver the PBGD gene into the AIP mouse model no enhancement of the endogenous PBGD activity in liver was detectable, despite the presence of the PBGD-plasmids as verified by PCR [15].

References