Advances in the molecular characterization of tryptophan hydroxylase

Mockus, Susan M.; Vrana, Kent E.

doi:10.1007/bf02761772

Cited by 93 publications

(74 citation statements)

References 136 publications

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“…4). Although neural TPH and recombinant enzymes were reportedly phosphorylated by PKA (reviewed in [38]), in the present study, we could not obtain positive evidence for PKA phosphorylation of the TPH from P-815 (Fig. 3).…”

Section: Phosphorylation Of Non-neural Tph In Vitrocontrasting

confidence: 83%

Proteasome‐driven turnover of tryptophan hydroxylase is triggered by phosphorylation in RBL2H3 cells, a serotonin producing mast cell line

Iida

Sawabe

Kojima

et al. 2002

European Journal of Biochemistry

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We previously demonstrated in mast cell lines RBL2H3 and FMA3 that tryptophan hydroxylase (TPH) undergoes very fast turnover driven by 26S-proteasomes [Kojima, M., Oguro, K., Sawabe, K., Iida, Y., Ikeda, R., Yamashita, A., Nakanishi, N. & Hasegawa, H. (2000) J. Biochem (Tokyo) 2000, 127,[121][122][123][124][125][126][127]. In the present study, we have examined an involvement of TPH phosphorylation in the rapid turnover, using non-neural TPH. The proteasome-driven degradation of TPH in living cells was accelerated by okadaic acid, a protein phosphatase inhibitor. Incorporation of 32 P into a 53-kDa protein, which was judged to be TPH based on autoradiography and Western blot analysis using anti-TPH serum and purified TPH as the size marker, was observed in FMA3 cells only in the presence of both okadaic acid and MG132, inhibitors of protein phosphatase and proteasome, respectively. In a cell-free proteasome system constituted mainly of RBL2H3 cell extracts, degradation of exogenous TPH isolated from mastocytoma P-815 cells was inhibited by protein kinase inhibitors KN-62 and K252a but not by H89. Consistent with the inhibitor specificity, the same TPH was phosphorylated by exogenous Ca 2+ /calmodulindependent protein kinase II in the presence of Ca 2+ and calmodulin but not by protein kinase A (catalytic subunit). TPH protein thus phosphorylated by Ca 2+ /calmodulindependent protein kinase II was digested more rapidly in the cell-free proteasome system than was the nonphosphorylated enzyme. These results indicated that the phosphorylation of TPH was a prerequisite for proteasome-driven TPH degradation.Keywords: tetrahydrobiopterin; CaM kinase II; proteasome target; ubiquitin ligase; enzyme turnover.Tryptophan hydroxylase (TPH, EC 1.14.16.4), a member of a family of pterin-dependent aromatic amino acid hydroxylases [1], catalyzes the conversion of L-tryptophan to 5-hydroxy-L-tryptophan. This reaction is the initial and rate-limiting step in the biosynthesis of serotonin [2][3][4][5]. TPH has been extensively purified from various sources such as bovine pineal gland [6], mouse mastocytoma [7,8], and mammalian brains [9][10][11]. Physicochemical, enzymic and immunochemical properties differed between TPHs of neural and non-neural tissue origin, and it is accepted that neural TPH might be a different entity from the non-neural enzyme [8,10,12,13]. Complimentary DNAs of TPH have been cloned from various sources but no differences or only trivial variation in amino acid sequences were found among them [14][15][16][17][18][19]. The molecular basis of differences between the neural and non-neural enzymes has not yet been explained.Both types of cytosolic environment should be studied further to detect differences in the control of gene expression, post-translational modification, and turnover of the enzyme protein in a tissue-specific way.We have demonstrated with RBL2H3, an established cell line that expresses TPH in culture while retaining many of the characteristics of mast cells, that: (a) cellular TPH activity was ...

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Section: Phosphorylation Of Non-neural Tph In Vitrocontrasting

confidence: 83%

Proteasome‐driven turnover of tryptophan hydroxylase is triggered by phosphorylation in RBL2H3 cells, a serotonin producing mast cell line

Iida

Sawabe

Kojima

et al. 2002

European Journal of Biochemistry

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“…In mammals, serotonin is synthesized from tryptophan in two steps involving L-tryptophan 5-hydroxylase and aromatic L-amino acid decarboxylase (Fig. 6) (28). Tryptophan hydroxylase belongs to a family of aromatic amino acid hydroxylases and requires iron and the coenzyme tetrahydropterin for catalytic activity (29).…”

Section: Discussionmentioning

confidence: 99%

Sekiguchi Lesion Gene Encodes a Cytochrome P450 Monooxygenase That Catalyzes Conversion of Tryptamine to Serotonin in Rice

Fujiwara

Maisonneuve

Isshiki

et al. 2010

Journal of Biological Chemistry

198

192

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Serotonin is a well known neurotransmitter in mammals and plays an important role in various mental functions in humans. In plants, the serotonin biosynthesis pathway and its function are not well understood. The rice sekiguchi lesion (sl) mutants accumulate tryptamine, a candidate substrate for serotonin biosynthesis. We isolated the SL gene by map-based cloning and found that it encodes CYP71P1 in a cytochrome P450 monooxygenase family. A recombinant SL protein exhibited tryptamine 5-hydroxylase enzyme activity and catalyzed the conversion of tryptamine to serotonin. This pathway is novel and has not been reported in mammals. Expression of SL was induced by the N-acetylchitooligosaccharide (chitin) elicitor and by infection with Magnaporthe grisea, a causal agent for rice blast disease. Exogenously applied serotonin induced defense gene expression and cell death in rice suspension cultures and increased resistance to rice blast infection in plants. We also found that serotonin-induced defense gene expression is mediated by the RacGTPase pathway and by the G␣ subunit of the heterotrimeric G protein. These results suggest that serotonin plays an important role in rice innate immunity.

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“…This observation confirmed the repeatedly discussed hypothesis of a second TPH isoform. 12,13 Using the TPH1 sequence as a query in a screening procedure of the Human Genome Database, the group of Walter et al 11 identified a new TPH isoform which they designated as second tryptophan hydroxylase isoform (TPH2) or neuronal TPH. The expression of both isoforms is partially exclusive.…”

mentioning

confidence: 99%

SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression

et al. 2004

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Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed singlenucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P ¼ 0.0012, global P ¼ 0.0051) and MD. Haplotype analysis produced additional support for association (Po0.0001, global P ¼ 0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.

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Advances in the molecular characterization of tryptophan hydroxylase

Cited by 93 publications

References 136 publications

Proteasome‐driven turnover of tryptophan hydroxylase is triggered by phosphorylation in RBL2H3 cells, a serotonin producing mast cell line

Proteasome‐driven turnover of tryptophan hydroxylase is triggered by phosphorylation in RBL2H3 cells, a serotonin producing mast cell line

Sekiguchi Lesion Gene Encodes a Cytochrome P450 Monooxygenase That Catalyzes Conversion of Tryptamine to Serotonin in Rice

SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression

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