Lindblad B, Lindstedt S, Steen G
Proc Natl Acad Sci U S A. 1977 Oct;74(10):4641-5. doi: 10.1073/pnas.74.10.4641.
The activity of the enzyme porphobilinogen synthase (EC 4.2.1.24) in erythrocytes from patients with hereditary tyrosinemia was less than 5% of that in a control group and the activity in liver tissue was less than 1% of the reported normal activity. Urine from patients with hereditary tyrosinemia contained an inhibitor that was isolated and identified as succinylacetone (4,6-dioxoheptanoic acid) by gas/liquid chromatography-mass spectrometry. Fresh urine samples contained succinylacetoacetate (3,5-dioxooctanedioic acid) as well as succinylacetone. The inhibition of porphobilinogen synthase explains the high excretion of 5-aminolevulinate observed in hereditary tyrosinemia. Succinylacetone and succinylacetoacetate presumably originate from maleylacetoacetate or fumarylacetoacetate, or both, and their accumulation indicates a block at the fumarylacetoacetase (EC 3.7.1.2) step in the degradation of tyrosine. We suggest that the severe liver and kidney damage in hereditary tyrosinemia may be due to the accumulation of these tyrosine metabolites and that the primary enzyme defect in hereditary tyrosinemia may be decreased activity of fumarylacetoacetase.
遗传性酪氨酸血症患者红细胞中胆色素原合酶（EC 4.2.1.24）的活性不到对照组的5%，肝组织中的活性不到报道的正常活性的1%。遗传性酪氨酸血症患者的尿液中含有一种抑制剂，通过气/液色谱-质谱法分离并鉴定为琥珀酰丙酮（4,6-二氧庚酸）。新鲜尿液样本中含有琥珀酰乙酰乙酸（3,5-二氧代辛二酸）以及琥珀酰丙酮。胆色素原合酶的抑制作用解释了遗传性酪氨酸血症中观察到的5-氨基乙酰丙酸的高排泄。琥珀酰丙酮和琥珀酰乙酰乙酸可能源自马来酰乙酰乙酸或富马酰乙酰乙酸中的一种或两种物质，它们的积累表明酪氨酸降解过程中富马酰乙酰乙酸酶（EC 3.7.1.2）步骤受阻。我们认为，遗传性酪氨酸血症中严重肝损伤和肾损伤可能归因于这些酪氨酸代谢产物的积累，遗传性酪氨酸血症中的原发性酶缺陷可能是富马酰乙酰乙酸酶活性降低。
