Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007095 (carcinoid)
 6,990 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated gastrointestinal absorption in six consecutive patients with metastatic serotonin-secreting carcinoid tumors. One patient had a consistent defect in fat absorption and two other patients malabsorbed fat during spontaneous or dopamine-induced exacerbation of the carcinoid syndrome. The steatorrhea of the patient with the persistent defect in fat absorption was reduced when tumor serotonin production was reduced by the tryptophan hydroxylase inhibitor parachlorophenylalanine. The six patients had normal hemoglobin levels and the serum concentration of the following urinary constituents was normal in most of the patients: albumin, carotene, 25-hydroxycalciferol, parathyroid hormone, calcitonin, calcium, phosphorous, osteogenous alkaline phosphatase, cholesterol, triglycerides, and serum lipoproteins. The excretion of the following urinary constituents was also normal in most of the patients: creatinine clearance, tubular reabsorption of phosphorous, calcium, D-xylose, cyclic 3'5' monophosphate and hydroxyproline. We conclude that patients with the carcinoid syndrome may have steatorrhea, and that their hyperserotoninemia plays a role in this process.
 ...
PMID:Gastrointestinal and metabolic function in patients with the carcinoid syndrome. 19 79

Although both carcinoid tumors and pheochromocytomas arise from neural crest origin, they are thought to each secrete distinctive monoamines; carcinoid tumors, which contain tryptophan hydroxylase, secrete serotonin, and pheochromocytomas, which contain tyrosine hydroxylase, may secrete dopamine (DA), norepinephrine (NE), or epinephrine (E). The purpose of this study was to determine if patients with carcinoid tumors have evidence of increased DA production. Of patients with serotonin-producing carcinoid tumors, 18%, 27%, and 35%, respectively, had increased urinary homovanillic acid (HVA) excretion (the principal metabolite of DA), urinary DA excretion, and plasma DA concentration. In contrast, none of the patients with nonserotonin-producing carcinoid tumors had evidence of increased DA production. Only 4% of patients with miscellaneous tumors had increased excretion of homovanillic acid or DA; none of the patients with miscellaneous tumors had increased plasma DA concentration. This study suggests that DA and HVA measurements may be useful in the evaluation of some patients with suspected carcinoid tumors.
 ...
PMID:Increased dopamine production in patients with carcinoid tumors. 397 52

Development of a rapid and sensitive radioassay has permitted study of the conversion of tryptophan to 5-hydroxytryptophan in mammalian tissues. Of normal tissues examined, beef and rat pineal gland contained the highest activity. This is the first direct demonstration of tryptophan hydroxylase in this hydroxyindole-rich tissue. Rat and rabbit brainstem and human carcinoid tumor also had quantities of enzyme that could be measured easily. The reaction requires a reduced pteridine and oxygen and is inhibired by Para-Chorophenylalanine.
 ...
PMID:Tryptophan hydroxylation: measurement in pineal gland, brainstem, and carcinoid tumor. 601 30

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.
 ...
PMID:Elevated aromatic-L-amino acid decarboxylase in human carcinoid tumors. 757 47

We report the isolation and the organization of the gene encoding human tryptophan hydroxylase (TPH) and an analysis of the corresponding mRNAs. The gene spans a region of 29 kilobases, which contains at least 11 exons and a variably spliced 5'-untranslated region (5'-UTR). The sequence of the coding region and the majority of the positions of the intron-exon boundaries of human TPH gene are very similar to those encoding human tyrosine hydroxylase and phenylalanine hydroxylase, the other members of the aromatic amino acid hydroxylase family. Phylogenetic analysis evidences the early divergence and the independent evolution of the three hydroxylase types. TPH cDNA cloning and anchored polymerase chain reaction revealed a diversity of the TPH mRNA, which is restricted to the 5'-UTR. Four TPH mRNA species were detected by Northern blot with pineal gland and carcinoid tumor RNAs. These messengers are transcribed from a single transcriptional initiation site, and their diversity results from differential splicing of three intron-like regions and of three exons located in the 5'-UTR. Analysis by S1 nuclease protection revealed that the intron-like regions in the 5'-UTR are mostly unspliced and that TPH mRNA species where the three intron-like regions are eliminated are present at low level in pineal gland and not detectable in carcinoid tumors.
 ...
PMID:The human tryptophan hydroxylase gene. An unusual splicing complexity in the 5'-untranslated region. 787 15

Rabbit and human brain tryptophan hydroxylase were cloned and expressed in Escherichia coli. Each of the respective cDNAs, including the complete coding sequence of tryptophan hydroxylase, was obtained by reverse transcription of rabbit or human brain mRNA and subcloned into the expression vector pET-3C. The expressed rabbit brain tryptophan hydroxylase activity, measured in the presence of tetrahydrobiopterin, represents approximately a 50-fold enhancement in yield (units/g tissue (wet wt) over that of a rabbit brain extract. Likewise, the level of expressed human brain tryptophan hydroxylase is approximately 57 times the average yield previously reported for a human brain homogenate and approximately 10-times the activity of homogenates of human raphe nucleus. The rabbit brain and pineal-derived tryptophan hydroxylase sequences varied by disparities in six amino acid residues (99% identity). The human carcinoid and brain peptide sequences varied by disparities in 18 amino acid residues (96% identity). Several properties of both expressed enzymes were studied and compared with those of native tryptophan hydroxylases.
 ...
PMID:Cloning and expression of rabbit and human brain tryptophan hydroxylase cDNA in Escherichia coli. 798 90

alpha-Fluoromethyl amino acids are enzyme-activated irreversible inhibitors of amino acid decarboxylases. Aromatic L-amino acid decarboxylase (AADC) is the enzyme responsible for the final step in the biosynthesis of both dopamine and serotonin via decarboxylation of L-dopa and 5-hydroxy-L-tryptophan, respectively. Our goal is to utilize antagonists of the serotonin-producing enzymes (tryptophan hydroxylase and AADC) as the basis for a chemotherapeutic approach to the treatment of carcinoid tumors, a rare tumor type characterized by the overproduction of serotonin. We report here an enantiospecific synthesis of alpha(S)-(fluoromethyl)tryptophan [(S)-11a] and alpha(S)-(fluoromethyl)-5-hydroxytryptophan [(S)-11b], as well as the (R)-enantiomers, based upon recent methodology involving the face-selective alkylation of cyclic tryptophan tautomers. Our synthetic route provided both enantiomers of 11a and 11b with greater than 97% enantiomeric purity based upon evaluation of the NMR spectra of their Mosher's acid derivatives. (S)-11a was evaluated as a substrate for P815 tryptophan hydroxylase and determined to have an apparent Km of 4.31 +/- 1.07 mM, essentially half the value previously reported for the racemic mixture of 11a with rat brain stem tryptophan hydroxylase. (R)-11a was not a substrate for P815 tryptophan hydroxylase. (S)-11b was evaluated as an enzyme-activated irreversible inhibitor of murine liver AADC and determined to have a KI of 24.3 +/- 3.01 microM and a k2 of 2.26 +/- 0.44 min-1. (R)-11b was not an inhibitor of murine liver AADC.
 ...
PMID:Enantiospecific syntheses of alpha-(fluoromethyl)tryptophan analogues: interactions with tryptophan hydroxylase and aromatic L-amino acid decarboxylase. 842 60

A mouse mastocytoma model was used to determine the biodistribution and tumour uptake of four radiopharmaceuticals developed to target the serotonin synthetic pathway in carcinoid tumours. Three of the compounds were competitive inhibitors of the rate-limiting enzyme of serotonin synthesis, tryptophan hydroxylase. Radiolabelled iodo-dL-phenylalanine (iodine-131 PIPA) was found to have the highest uptake and tumour-to-liver ratio. Four patients with known carcinoid tumours were then injected with 0.5 mCi 131I-PIPA and imaged at 1, 4, 24 and 48 h post-injection. The radiopharmaceutical, however, failed to localize in the known tumour sites. This result was in contrast to the authors experience of 131I- and 123I-MIBG imaging of carcinoid tumours. Seven patients with known metastatic carcinoid tumours, two patients with symptoms of recurrence following tumour resection, one patient with completely resected disease, and two patients with a flushing syndrome of uncertain aetiology were studied with 131I-MIBG. Three of the seven patients with known metastatic disease had positive 131I-MIBG scans. Both patients with clinical evidence of recurrent disease had negative scans, as did the patient who was considered to have had complete resection of her primary tumour. The two patients with idiopathic flushing syndrome also had negative scans. Among seven patients imaged with 123I-MIBG there were four true-negative scans and one false-negative, the latter in a patient with biochemical and CT evidence of recurrence. In a seventh patient with distant metastases there was variable uptake in some of the lesions. Four patients were studied with indium-111 pentetreotide . Two patients with metastatic carcinoid disease had positive scans, although hepatic metastases were not seen in one. Another two with idiopathic flushing syndrome had normal studies. The literature suggests that up 50% of carcinoid tumour cases are detected with 131I-MIBG, compared to a sensitivity of 87% reported with somatostatin receptor imaging using 111In-pentetreotide. The experience with 123I-MIBG is much less extensive. The mechanisms of carcinoid tumour localization for each of the three classes of radiotracers are discussed and contrasted to their varying sensitivities. The relative success of 131I-MIBG and 111In-pentetreotide relative to 131I-PIPA may be related to the fact that 131I-MIBG is actively taken up and stored by the enterochromaffin cells of the tumours and 111In-pentetreotide binds to cell surface receptors, whereas 131I-PIPA binds to tryptophan hydroxylase, which may be present in quantities too small to permit tumours to be imaged.
 ...
PMID:Successful and unsuccessful approaches to imaging carcinoids: comparison of a radiolabelled tryptophan hydroxylase inhibitor with a tracer of biogenic amine uptake and storage, and a somatostatin analogue. 892 46

The expression of tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin, is described in a case of a 35 year-old patient with metastatic jejunal carcinoid. Immunohistochemically, monoclonal anti-tryptophan hydroxylase antibodies positively identified liver metastases of a neuroendocrine tumor. The cellular distribution of tryptophan hydroxylase was restricted exclusively to the cytoplasm of carcinoid cells, where it was found in large amounts. By means of immunoblotting, anti-tryptophan hydroxylase antibodies detected in samples from carcinoid tissue two closely migrating polypeptide bands with molecular weights of 26 kDa and 29 kDa, respectively. These two protein bands appear to represent proteolytically degraded polypeptides, since tryptophan hydroxylase is known for its extreme unstability in vitro. In our case, the immunohistochemical and biochemical identification of tryptophan hydroxylase in liver lesions of a neuroendocrine tumor permitted the correct diagnosis of a metastatic carcinoid.
 ...
PMID:Tryptophan hydroxylase antibodies used in the diagnosis of carcinoid. 984 98

The first step in the biosynthesis of melatonin in the pineal gland is the hydroxylation of tryptophan to 5-hydroxytryptophan. A cDNA of human tryptophan hydroxylase (TPH) was cloned from a library of human pineal gland and expressed in Escherichia coli. This cDNA sequence is identical to the cDNA sequence published from the human carcinoid tissue [1]. This human pineal hydroxylase gene encodes a protein of 444 amino acids and a molecular mass of 51 kDa estimated for the purified enzyme. Tryptophan hydroxylase from human brainstem exhibits high sequence homology (93% identity) with the human pineal hydroxylase. The recombinant tryptophan hydroxylase exists in solution as tetramers. The expressed human pineal tryptophan hydroxylase has a specific activity of 600 nmol/min/mg when measured in the presence of tetrahydrobiopterin and L-tryptophan. The enzyme catalyzes the hydroxylation of tryptophan and phenylalanine at comparable rates. Phosphorylation of the hydroxylase by protein kinase A or calmodulin-dependent kinase II results in the incorporation of 1 mol of phosphate/mol of subunit, but this degree of phosphorylation leads to only a modest (30%) increase in BH(4)-dependent activity when assayed in the presence of 14-3-3. Rapid scanning ultraviolet spectroscopy has revealed the formation of the transient intermediate compound, 4alpha-hydroxytetrahydrobiopterin, during the hydroxylation of either tryptophan or phenylalanine catalyzed by the recombinant pineal TPH.
 ...
PMID:Cloning and expression of recombinant human pineal tryptophan hydroxylase in Escherichia coli: purification and characterization of the cloned enzyme. 1052 50


1 2 Next >>