Elevated aromatic-L-amino acid decarboxylase in human carcinoid tumors

Abstract

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.