Functional Interactions Between GTP Cyclohydrolase I and Tyrosine Hydroxylase in<i>Drosophila</i>

Krishnakumar, Sujatha; Burton, Denise; Rasco, Jane F.; Chen, Xiongying; O’Donnell, Janis M.

doi:10.3109/01677060009083474

Cited by 40 publications

(54 citation statements)

References 37 publications

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“…This cofactor is required for the conversion of tyrosine to dopamine (37), which has at least two possible roles in immunity. First, dopamine is one of two main Drosophila catecholamines, which are important for the stress response in both insects and mammals (38).…”

Section: Discussionmentioning

confidence: 99%

Immune Activation of NF-κB and JNK Requires Drosophila TAK1

Silverman

Zhou²,

Erlich

et al. 2003

Journal of Biological Chemistry

243

230

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Section: Discussionmentioning

confidence: 99%

Immune Activation of NF-κB and JNK Requires Drosophila TAK1

Silverman

Zhou²,

Erlich

et al. 2003

Journal of Biological Chemistry

243

230

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“…As in mammals, these studies have demonstrated that GTPCH and TH co-localize within Drosophila neurons and that the activity of TH is precisely correlated with the in vivo activity of GTPCH (22), whereas coimmunoprecipitation studies suggest that GTPCH and TH from head extracts physically associate (22). Interestingly, it has been observed that homozygous Punch mutants exhibit phenotypes similar to those of pale homozygotes (23,24), whereas biochemical analyses of heterozygous Punch mutant flies reveal a reduction in the in vivo activity of TH due to reduced levels of the cofactor, BH 4 (22). Surprisingly, the introduction of exogenous BH 4 fails to restore full TH activity in extracts of the heads of Punch mutants despite the fact that TH protein levels are unaffected by Punch mutations.…”

mentioning

confidence: 99%

Direct Binding of GTP Cyclohydrolase and Tyrosine Hydroxylase

Bowling

Huang

et al. 2008

Journal of Biological Chemistry

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The signaling functions of dopamine require a finely tuned regulatory network for rapid induction and suppression of output. A key target of regulation is the enzyme tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, which is activated by phosphorylation and modulated by the availability of its cofactor, tetrahydrobiopterin. The first enzyme in the cofactor synthesis pathway, GTP cyclohydrolase I, is activated by phosphorylation and inhibited by tetrahydrobiopterin. We previously reported that deficits in GTP cyclohydrolase activity in Drosophila heterozygous for mutant alleles of the gene encoding this enzyme led to tightly corresponding diminution of in vivo tyrosine hydroxylase activity that could not be rescued by exogenous cofactor. We also found that the two enzymes could be coimmunoprecipitated from tissue extracts and proposed functional interactions between the enzymes that extended beyond provision of cofactor by one pathway for another. Here, we confirm the physical association of these enzymes, identifying interacting regions in both, and we demonstrate that their association can be regulated by phosphorylation. The functional consequences of the interaction include an increase in GTP cyclohydrolase activity, with concomitant protection from endproduct feedback inhibition. In vivo, this effect would in turn provide sufficient cofactor when demand for catecholamine synthesis is greatest. The activity of tyrosine hydroxylase is also increased by this interaction, in excess of the stimulation resulting from phosphorylation alone. V max is elevated, with no change in K m . These results demonstrate that these enzymes engage in mutual positive regulation.

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“…We reasoned that because GTPCH is rate limiting for the synthesis of BH 4 in Drosophila (Krishnakumar et al, 2000) and the cofactor, in turn, is limiting for DA synthesis, overexpression should elevate both cofactor and DA levels. The pharmacological analyses described above led to the prediction that DA overexpression should lead to greater resistance to the effects of paraquat if its effects were initially limited to dopaminergic cells.…”

Section: Paraquat Causes Selective Loss Of Da Neuron Clustersmentioning

confidence: 99%

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Chaudhuri¹,

Bowling²,

Funderburk³

et al. 2007

J. Neurosci.

194

216

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Catastrophic loss of dopaminergic neurons is a hallmark of Parkinson's disease. Despite the recent identification of genes associated with familial parkinsonism, the etiology of most Parkinson's disease cases is not understood. Environmental toxins, such as the herbicide paraquat, appear to be risk factors, and it has been proposed that susceptibility is influenced by genetic background. The genetic model organism Drosophila is an advantageous system for the identification of genetic susceptibility factors. Genes that affect dopamine homeostasis are candidate susceptibility factors, because dopamine itself has been implicated in neuron damage. We find that paraquat can replicate a broad spectrum of parkinsonian behavioral symptoms in Drosophila that are associated with loss of specific subsets of dopaminergic neurons. In parallel with epidemiological studies that show an increased incidence of Parkinson's disease in males, male Drosophila exhibit paraquat symptoms earlier than females. We then tested the hypothesis that variation in dopamine-regulating genes, including those that regulate tetrahydrobiopterin, a requisite cofactor in dopamine synthesis, can alter susceptibility to paraquatinduced oxidative damage. Drosophila mutant strains that have increased or decreased dopamine and tetrahydrobiopterin production exhibit variation in susceptibility to paraquat. Surprisingly, protection against the neurotoxicity of paraquat is conferred by mutations that elevate dopamine pathway function, whereas mutations that diminish dopamine pools increase susceptibility. We also find that loss-of-function mutations in a negative regulator of dopamine production, Catecholamines-up, delay the onset of neurological symptoms, dopaminergic neuron death, and morbidity during paraquat exposure but confer sensitivity to hydrogen peroxide.

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Functional Interactions Between GTP Cyclohydrolase I and Tyrosine Hydroxylase inDrosophila

Cited by 40 publications

References 37 publications

Immune Activation of NF-κB and JNK Requires Drosophila TAK1

Immune Activation of NF-κB and JNK Requires Drosophila TAK1

Direct Binding of GTP Cyclohydrolase and Tyrosine Hydroxylase

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

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