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

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.
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PMID:The human tryptophan hydroxylase gene. An unusual splicing complexity in the 5'-untranslated region. 787 15

Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements - SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition. However, selectivity over non-pathogenic enzyme family members, TPH2, phenylalanine hydroxylase, and tyrosine hydroxylase has hampered therapeutic development. Here we describe the site/sequence, biochemical, and biophysical characterization of a novel allosteric site on TPH1 through which selectivity over TPH2 and related aromatic amino acid hydroxylases is achieved. We demonstrate the mechanism of action by which novel compounds selectively inhibit TPH1 using surface plasma resonance and enzyme competition assays with both tryptophan ligand and BH4 co-factor. We demonstrate 15-fold greater potency within a human carcinoid cell line versus the most potent known TPH1/2 non-specific inhibitor. Lastly, we detail a novel canine in vivo system utilized to determine effective biologic inhibition of newly synthesized 5-HT. These findings are the first to demonstrate TPH1-selective inhibition and may pave the way to a truly effective means to reduce pathologic 5-HT and thereby treat complex remodeling diseases such as PAH.
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PMID:Identification of a Novel Allosteric Inhibitory Site on Tryptophan Hydroxylase 1 Enabling Unprecedented Selectivity Over all Related Hydroxylases. 2852 83