Elevated aromatic-L-amino acid decarboxylase in human carcinoid tumors.
The carcinoid neoplasm is marked by excessive serotonin, synthesized by the conversion of tryptophan (Trp) to 5-hydroxytryptophan by tryptophan hydroxylase (TPH) (EC 1.14.16.4) and decarboxylation of 5-hydroxytryptophan by aromatic-L-amino acid decarboxylase (AAAD) (EC 4.1.1.28). Because almost no biochemical data were available on human carcinoid TPH and AAAD, we have characterized these enzymes as a preliminary step to developing mechanism-based agents selective against carcinoid tumors. TPH was detected in all fourteen carcinoids analyzed [Km = 185 +/- 17 microM (mean +/- SEM); Vmax = 2.4 +/- 1.2 nmol/hr/mg protein]. AAAD was detected in thirteen tumors (Km = 45 +/- 6.7 microM; Vmax = 11 +/- 2.0 nmol/min/mg protein). In a subset of hepatic metastatic tumors obtained with adjacent normal liver, the Km and Vmax of TPH (N = 6) and the Km of AAAD (N = 7) were comparable in both tissues. However, the Vmax of carcinoid AAAD was 50-fold higher (P < 0.002) than that in normal liver (13 +/- 3.1 vs 0.26 +/- 0.04 nmol/min/mg protein). Western immunoblot analysis indicated that AAAD polypeptide content of carcinoid tumor was > 20-fold higher than in adjacent normal liver. These results suggest that AAAD might be an appropriate target for enzyme-activated cytotoxic agents for carcinoid tumors.
Gilbert
J A
JA
Department of Oncology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Bates
L A
LA
Ames
M M
MM
D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000032:analysis*; D002276:Carcinoid Tumor / Q000201:enzymology* / Q000556:secondary; D006801:Humans; D007414:Intestinal Neoplasms / Q000201:enzymology*; D008099:Liver / Q000201:enzymology; D008113:Liver Neoplasms / Q000201:enzymology / Q000556:secondary; D051379:Mice; D014365:Tryptophan Hydroxylase / Q000032:analysis*; D014407:Tumor Cells, Cultured
D014365:Tryptophan Hydroxylase; D001142:Aromatic-L-Amino-Acid Decarboxylases