Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme
Porphyrinogen carboxy-lyase is an enzyme that sequentially decarboxylates uroporphyrinogen III (8-COOH) to yield coproporphyrinogen III (4-COOH). In mammals this enzyme activity is impaired by hexachlorobenzene treatment, through generation of an enzyme inhibitor. The interaction of porphyrinogen ca...
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todo:paper_10399712_v47_n6_p945_DeCatabbi2023-10-03T15:57:39Z Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme De Catabbi, S.B. De Calmanovici, R.W. Minutolo, C. Aldonatti, C. De Viale, L.C.S.M. Hexachlorobenzene Porphyria Porphyrinogens Porphyrins Uroporphyrinogen Uroporphyrinogen decarboxylase inhibitor hexachlorobenzene liver enzyme porphyrinogen uroporphyrinogen decarboxylase animal experiment animal tissue article decarboxylation enzyme active site female liver nonhuman porphyria rat Animals Arginine Binding Sites Carboxy-Lyases Enzyme Inhibitors Female Hexachlorobenzene Humans Liver Porphyrias Porphyrinogens Rats Rats, Wistar Uroporphyrinogens Animalia Mammalia Porphyrinogen carboxy-lyase is an enzyme that sequentially decarboxylates uroporphyrinogen III (8-COOH) to yield coproporphyrinogen III (4-COOH). In mammals this enzyme activity is impaired by hexachlorobenzene treatment, through generation of an enzyme inhibitor. The interaction of porphyrinogen carboxy-lyase inhibitor, extracted from the liver of hexachlorobenzene-treated rats, with substrate decarboxylation sites on the enzyme, was studied using four different carboxylated substrates belonging to the isomeric III series of naturally-formed porphyrinogens containing 8-, 7-, 6- and 5-COOH. Similar inhibitor effects were elicited against all the substrates assayed, with the exception of pentacarboxyporphyrinogen III in which decarboxylation was not inhibited to same extent. Enzyme protection assays in the presence of the different substrates, indicated that each porphyrinogen protects its own decarboxylation from inhibitor action. Preincubation of the inhibitor with normal enzyme increased its inhibitory effect. On the other hand, preincubation of both enzyme and inhibitor with superoxide dismutase or mannitol, did not alter inhibitory activity. Preincubation of the inhibitor with a number showed that only arginine and its derivative Nα-Benzoyl-L-Arginine interact with the inhibitor, noticeably reducing its ability to inhibit porphyrinogen carboxy-lyase. Albumin, histidine, serine, cysteine and imidazol, were unable to quench inhibitor activity. The present results indicate that the inhibitor acts at the binding site of each porphyrinogen. Taking into account that arginine is related to enzyme activity, and that histidine is found at the binding site of the substrates, the results suggest that the inhibitor could bind to arginine residues, blocking the access of substrates to histidine and altering the adequate orientation for decarboxylation by masking the positively charged active site necessary for porphyrinogen binding to the enzyme. In addition an indirect effect of the inhibitor mediated through free radicals could be discarded. Fil:Minutolo, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_10399712_v47_n6_p945_DeCatabbi |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Hexachlorobenzene Porphyria Porphyrinogens Porphyrins Uroporphyrinogen Uroporphyrinogen decarboxylase inhibitor hexachlorobenzene liver enzyme porphyrinogen uroporphyrinogen decarboxylase animal experiment animal tissue article decarboxylation enzyme active site female liver nonhuman porphyria rat Animals Arginine Binding Sites Carboxy-Lyases Enzyme Inhibitors Female Hexachlorobenzene Humans Liver Porphyrias Porphyrinogens Rats Rats, Wistar Uroporphyrinogens Animalia Mammalia |
| spellingShingle |
Hexachlorobenzene Porphyria Porphyrinogens Porphyrins Uroporphyrinogen Uroporphyrinogen decarboxylase inhibitor hexachlorobenzene liver enzyme porphyrinogen uroporphyrinogen decarboxylase animal experiment animal tissue article decarboxylation enzyme active site female liver nonhuman porphyria rat Animals Arginine Binding Sites Carboxy-Lyases Enzyme Inhibitors Female Hexachlorobenzene Humans Liver Porphyrias Porphyrinogens Rats Rats, Wistar Uroporphyrinogens Animalia Mammalia De Catabbi, S.B. De Calmanovici, R.W. Minutolo, C. Aldonatti, C. De Viale, L.C.S.M. Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme |
| topic_facet |
Hexachlorobenzene Porphyria Porphyrinogens Porphyrins Uroporphyrinogen Uroporphyrinogen decarboxylase inhibitor hexachlorobenzene liver enzyme porphyrinogen uroporphyrinogen decarboxylase animal experiment animal tissue article decarboxylation enzyme active site female liver nonhuman porphyria rat Animals Arginine Binding Sites Carboxy-Lyases Enzyme Inhibitors Female Hexachlorobenzene Humans Liver Porphyrias Porphyrinogens Rats Rats, Wistar Uroporphyrinogens Animalia Mammalia |
| description |
Porphyrinogen carboxy-lyase is an enzyme that sequentially decarboxylates uroporphyrinogen III (8-COOH) to yield coproporphyrinogen III (4-COOH). In mammals this enzyme activity is impaired by hexachlorobenzene treatment, through generation of an enzyme inhibitor. The interaction of porphyrinogen carboxy-lyase inhibitor, extracted from the liver of hexachlorobenzene-treated rats, with substrate decarboxylation sites on the enzyme, was studied using four different carboxylated substrates belonging to the isomeric III series of naturally-formed porphyrinogens containing 8-, 7-, 6- and 5-COOH. Similar inhibitor effects were elicited against all the substrates assayed, with the exception of pentacarboxyporphyrinogen III in which decarboxylation was not inhibited to same extent. Enzyme protection assays in the presence of the different substrates, indicated that each porphyrinogen protects its own decarboxylation from inhibitor action. Preincubation of the inhibitor with normal enzyme increased its inhibitory effect. On the other hand, preincubation of both enzyme and inhibitor with superoxide dismutase or mannitol, did not alter inhibitory activity. Preincubation of the inhibitor with a number showed that only arginine and its derivative Nα-Benzoyl-L-Arginine interact with the inhibitor, noticeably reducing its ability to inhibit porphyrinogen carboxy-lyase. Albumin, histidine, serine, cysteine and imidazol, were unable to quench inhibitor activity. The present results indicate that the inhibitor acts at the binding site of each porphyrinogen. Taking into account that arginine is related to enzyme activity, and that histidine is found at the binding site of the substrates, the results suggest that the inhibitor could bind to arginine residues, blocking the access of substrates to histidine and altering the adequate orientation for decarboxylation by masking the positively charged active site necessary for porphyrinogen binding to the enzyme. In addition an indirect effect of the inhibitor mediated through free radicals could be discarded. |
| format |
JOUR |
| author |
De Catabbi, S.B. De Calmanovici, R.W. Minutolo, C. Aldonatti, C. De Viale, L.C.S.M. |
| author_facet |
De Catabbi, S.B. De Calmanovici, R.W. Minutolo, C. Aldonatti, C. De Viale, L.C.S.M. |
| author_sort |
De Catabbi, S.B. |
| title |
Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme |
| title_short |
Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme |
| title_full |
Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme |
| title_fullStr |
Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme |
| title_full_unstemmed |
Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme |
| title_sort |
porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme |
| url |
http://hdl.handle.net/20.500.12110/paper_10399712_v47_n6_p945_DeCatabbi |
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