On the enzymic defects in hereditary tyrosinemia

Area of Science:

• Biochemistry
• Metabolic Disorders
• Enzymology

Background:

• Hereditary tyrosinemia is a genetic disorder affecting tyrosine metabolism.
• Patients exhibit severe liver and kidney damage.
• The precise enzymatic defect and accumulating metabolites are not fully understood.

Purpose of the Study:

• To investigate the enzymatic activity in hereditary tyrosinemia.
• To identify inhibitors in patient urine.
• To elucidate the metabolic block and its consequences.

Main Methods:

• Enzyme activity assays in erythrocytes and liver tissue.
• Urine inhibitor isolation and identification using gas/liquid chromatography-mass spectrometry.
• Analysis of tyrosine metabolite accumulation.

Main Results:

• Porphobilinogen synthase activity was significantly reduced (<5% in erythrocytes, <1% in liver).
• Succinylacetone (4,6-dioxoheptanoic acid) was identified as a potent inhibitor in patient urine.
• Succinylacetoacetate (3,5-dioxooctanedioic acid) was also detected in fresh urine samples.

Conclusions:

• Inhibition of porphobilinogen synthase by succinylacetone explains 5-aminolevulinate excretion.
• Accumulation of succinylacetone and succinylacetoacetate indicates a block in tyrosine degradation at the fumarylacetoacetase step.
• Reduced fumarylacetoacetase activity is proposed as the primary defect, leading to toxic metabolite accumulation and organ damage.