ELEVATED AROMATIC-L-AMINO ACID DECARBOXYLASE IN HUMAN CARCINOID-TUMORS
ELEVATED AROMATIC-L-AMINO ACID DECARBOXYLASE IN HUMAN CARCINOID-TUMORS
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DOI：
10.1016/0006-2952(95)02006-x
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发表时间：
1995-09-07
影响因子：
5.8
通讯作者：
AMES, MM
中科院分区：
文献类型：
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作者：
GILBERT, JA;BATES, LA;AMES, MM
类癌肿瘤的特征是过量的5-羟色胺，通过色氨酸羟化酶（TPH）（EC 1.14.16.4）将色氨酸（Trp）转化为5-羟基色氨酸，并通过芳香族-L-氨基酸脱羧酶（AAAD）（EC 4.1.1.28）将5-羟基色氨酸脱羧而合成。由于几乎没有关于人类类癌TPH和AAAD的生物化学数据，我们已经将这些酶的特征描述为开发针对类癌肿瘤的选择性基于机制的药物的初步步骤。在分析的所有14种类癌中均检测到TPH [K-m = 185 +/- 17 μ M（平均值+/- SEM）; V-max = 2.4 + 1.2 nmol/hr/mg蛋白]。在13个肿瘤中检测到AAAD（K-m = 45 +/- 6.7 μ M; V-max = 11 +/- 2.0 nmol/min/mg蛋白）。在从邻近正常肝脏获得的肝转移瘤亚组中，TPH（N = 6）的Km和V-max与AAAD（N = 7）的Km在两种组织中相当。然而，类癌AAAD的Vmax是正常肝脏的50倍（P < 0.002）（13 +/- 3.1 vs 0.26 +/- 0.04 nmol/min/mg蛋白）。Western免疫印迹分析表明类癌组织中AAAD多肽含量比癌旁正常肝组织高20倍以上。这些结果表明AAAD可能是酶激活细胞毒性药物治疗类癌肿瘤的合适靶点。
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 mu M (mean +/- SEM); V-max = 2.4 + 1.2 nmol/hr/mg protein]. AAAD was detected in thirteen tumors (K-m = 45 +/- 6.7 mu M; 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.