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 [ K m = 185 ± 17 μM (mean ± SEM); V max = 2.4 ± 1.2 nmol/hr/mg protein]. AAAD was detected in thirteen tumors ( K m = 45 ± 6.7 μM; V max = 11 ± 2.0 nmol/min/mg protein). In a subset of hepatic metastatic tumors obtained with adjacent normal liver, the K m and V max of TPH (N = 6) and the K m of AAAD (N = 7) were comparable in both tissues. However, the V max 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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have