Uroporphyrinogen decarboxylase and

Woods JS, Fowler BA (1987) Metal alteration of uroporphyrinogen decarboxylase and coproporphyrinogen oxidase. Ann N Y Acad Sci 514 55-64 Woods JS, Southern MR (1989) Studies on the etiology of trace metal-induced porphyria effects of porphyrinogenic metals on coproporphyrinogen oxidase in rat liver and kidney. Toxicol Appl Pharmacol 97 183-190 Woods JS, Miller HD (1993) Quantitative measurement of porphyrins in biological tissues and evaluation of tissue porphyrins during toxicant exposures. Fundam Appl Toxicol 21 291-297... 

Deficiencies of other enzymes in the heme pathway produce porphyrias in which photosensitivity is a common finding. Chronic inflammation to overt blistering and shearing in exposed areas of the skin characterize these porphyrias. The most common is porphyria cutanea tarda (deficiency of uroporphyrinogen decarboxylase). 

The first porphyrin intermediate of the biosynthetic pathway is uroporphyrinogen, which is stepwise decarboxylated by uroporphyrinogen decarboxylase to heptacarboxy-, hexacarboxy-, pentacarboxy-, and coproporphyrinogen. This latter compound proceeds, as indicated in Fig. 7.3.1, to protoporphyrinogen and protoporphyrin. The oxidized uroporphyrin and its decarboxylation products up to coproporphyrin are assayed in urine. Coproporphyrin and the further downstream intermediaries can be recovered from feces as described below. 

The first of these decarboxylations is catalyzed by the cytoplasmic uroporphyrinogen decarboxylase, which removes the carboxylate groups of the four acetate side chains sequentially from the D, A, B, and C rings.395-3963 A possible mechanism, utilizing a tautomerized ring, is illustrated in the accompanying structural formula. 

Jones KG, Sweeney GD. 1977. Association between induction of aryl hydrocarbon hydroxylase and depression of uroporphyrinogen decarboxylase activity. Res Commun Chem Pathol Pharmacol 17 631-637. 

Uroporphyrin I and coproporphyrin I will be present in the urine. In the absence of uroporphyrinogen cosynthase, hydroxymethyl bilane will spontaneously cyclyze into uroporphyrinogen I. Some of it will be oxidized to uroporphyrin I. Some will be decarboxylated by uroporphyrinogen decarboxylase to coproporphyrinogen I and then oxidized to coproporphyrin I. None of these will be degraded by heme oxidase. 

Figure 3 The synthesis of heme from glycine and sucdnyl-CoA. The enzymes are ALAS, S-aminolevulinic acid (ALA) synthase ALAD, S-aminolevulinic acid dehydratase PBGD, porphobilinogen deaminase UROIIIS, uroporphyrinogen III synthase UROD, uroporphyrinogen decarboxylase CPO, coproporphyrinogen oxidase PPO, protoporphyrinogen oxidase and FECH, ferrochelatase.

Disorder of haem synthesis Inhibition of hepatic coproporphy-rinogen-oxidase and uroporphyrinogen-decarboxylase can give... 

This is a very rare form of chronic hepatic porphyria. As with PCT, the enzymatic defect is a deficiency of uroporphyrinogen decarboxylase. However, the genetic defect is homozygous. It may also be caused by exogenous factors. HEP manifests in early childhood with high photosensitivity, sclerodermia, hypertrichosis and anaemia. The liver shows red fluorescence. Histologically, siderosis and non-specific hepatitis are found. Development of cirrhosis is possible. No effective therapy is known. (314, 316)... 

In porphyria cutanea tarda, iron deposition in the liver is generally low to moderate, predominantly in the hepa-tocytes of the acinar periphery. The cause is thought to be reduced activity of uroporphyrinogen decarboxylase resulting in decreased synthesis of porphyrin and haem. However, this variant of hepatic siderosis only becomes manifest as a result of various triggering factors. Treatment is also based on venesection. 

Egger, N.G., Goeger, D.E., Payne, D.A., Miskovsky, E.P., Weinman, S.A., Anderson, K.E. Porphyria cutanea tarda. Multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Dig. Dis. Sci. 2002 47 419-426... 

The genes for all the enzymes of human heme biosynthesis have been characterized (Table 32-2), and the structures of 5-aminolevulinic acid dehydratase (ALAD), hydroxymethyl-bilane synthase (HMBS), uroporphyrinogen-III synthase (UROS), uroporphyrinogen decarboxylase (UROD), and ferrochelatase (FECH) have been determined by x-ray crys-tallography. - - ... 

Christiansen L, Ged C, Hombrados I, Brons-Poulsen J, Fontanellas A, de Verneuil H, et al. Screening for mutations in the uroporphyrinogen decarboxylase gene using denaturing gradient gel electrophoresis. Identification and characterization of six novel mutations associated with familial PCT. Hum Mutat 1999 14 222-32. 

Luo J, Lim CK. Order of uroporphyrinogen-ill decarboxylations on incubation of porphobilinogen and uroporphyrinogen-III with erythrocyte uroporphyrinogen decarboxylase. Biochem J 1993 289, 519-523. 

Mendez M, Sorkin L, Rossetti MV, Astrin KH, del C Batlle AM, Parera VE, et al. Familial porphyria cutanea tarda characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis aUeles. Am J Hum Genet 1998 63 1363-75. 

Mukerji SK, Pimstone NR. Uroporphyrinogen decarboxylases from human erythrocytes purification, complete separation and partial characterization of the two isoenzymes. Int J Biochem 1992 24 105-19. 

Franklin MR, Phillips JD, Kushner JP. 1997. Cytochrome P450 induction, uroporphyrinogen decarboxylase depression, porphyin accumulation and excretion, and gender influence in a 3-week rat model of porphyria cutanea tarda. Toxicol Appl Pharmacol 147 289-299. 

Chen, T.C. and G.W. Miller Purification and characterization of uroporphyrinogen decarboxylase from tobacco leaves Plant Cell Physiol. 15 (1974) 993-1005. 

Smith et al. (1995) reported synergy of iron in the toxicity and carcinogenicity of PCBs. An iron overload induced liver tumors and other lesions in mice. A single dose of iron potentiated PCB mixture Aroclor 1254 to induce porphyria by inhibition at the uroporphyrinogen decarboxylase stage of hepatic haem biosynthesis. The authors proposed an iron-catalyzed oxidative stress mechanism suggesting a link between porphyria and cancer. 

Uroporphyrinogen decarboxylase (EC 4.1.1.37). The enzyme is unstable. Increased fecal excretion of uroporphyrin, porphyrins possessing 7 carboxylic add groups, copropoiphyrin and isocoproporphyrin. Phot ennatosis. Hepatic siderosis. Risk of primary hepatocellular carcinoma greatly increased. Treatment by phlebotomy. Autosomal dominant. The condition may also be induced by exposure to halogena-ted aromatic hydrocarbons (e.g. polychlorinated biphenyls, hexachlorobenzene). 

Porphyria cutanea tarda (PCX) has been reported in humans following TCDD exposure (Bleiberg et al. 1964). However, normal urine porphyrin levels have been observed from individuals with severe chloracnegen exposure (Strik 1979). TCDD is a porphyrinogen in animal models and inhibits uroporphyrinogen decarboxylase, the enzyme precipitating PCX in some patients (Mukerjee 1998). 

Fig. 1. Heme biosynthetic pathway. Steps are catalyzed by 7, -aminolevulinic acid (ALA) synthetase 2, ALA dehydratase 3, uroporphyrinogen I synthetase (PBG deaminase) 4, uroporphyrinogen III cosynthetase 5, uroporphyrinogen decarboxylase 6, coproporphyrinogen oxidase 7, protoporphyrinogen oxidase and 8, ferrochelatase (heme synthetase)...

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