Disease relevance of Pu

• Axon-tracing experiments demonstrated that neurons expressing a given Gr gene project their axons to a spatially restricted domain of the subesophageal ganglion in the fly brain [1].
• These studies demonstrate that micromolar levels of reduced pterins may have regulatory effects on GTP cyclohydrolase I and that a mouse mutant is available that has low enough activity to be considered as a model for human atypical phenylketonuria [2].
• The deduced amino acid sequence of Tetrahrymena GTP cyclohydrolase I showed sequence identity with that of Escherichia coli (55%) [3].

High impact information on Pu

• A Gr receptor is required for response to the sugar trehalose in taste neurons of Drosophila [4].
• We recently identified from the Drosophila genome database a large family of G protein-coupled receptor genes, the Gr genes, and predicted that they encode taste receptors on the basis of their structure and specificity of expression [4].
• GTP cyclohydrolase is composed of a highly conserved homodecameric catalytic core and non-conserved N-terminal domains proposed to be regulatory sites [5].
• Mammalian GTP cyclohydrolase is subject to end-product inhibition via an associated regulatory protein and to positive regulation via phosphorylation, although target residues are unknown [5].
• The enzyme GTP cyclohydrolase I, which catalyzes the first step in the pteridine biosynthetic pathway, has been purified by at least 4400-fold from Drosophila melanogaster [6].

Biological context of Pu

• Although enzyme activity cannot be detected prior to larval stages, the locus must also have earlier functions since most homozygous Pu mutants die during embryogenesis [7].
• Eleven chromosomal deficiencies and several rearrangements in the Pu-tud region of chromosome 2R have been generated and examined cytologically [8].
• The activity of GTP CH is shown to be closely correlated with the number of Pu+ genes in the genome [9].
• Defects in the expression of the protein in Punch maternal effect mutants correlate well with the early phenotypes [10].
• As syncytial blastoderm nuclear divisions proceed, Punch protein levels decrease and disappear by cellularization [10].

Anatomical context of Pu

• We show that GTP cyclohydrolase and tyrosine hydroxylase (TH) are co-localized in the Drosophila central nervous system [11].

Associations of Pu with chemical compounds

• We report the characterisation of the serotonin content of individual Drosophila embryos, progeny from flies heterozygous for mutations in genes that are involved in the serotonin synthesis pathway and include the GTP-cyclohydrolase, tryptophan hydroxylase and DOPA decarboxylase loci [12].
• Defined functions of the locus include a role in embryonic nuclear divisions using initially a maternal Pu product, the synthesis of pterin cofactors that are required for catecholamine biosynthesis beginning in late embryogenesis, and the production of pterin-screening pigments in the developing adult eye [13].
• GTP cyclohydrolase I (GCH) is the rate-controlling enzyme in the production of tetrahydrobiopterin (BH4) that is essential for the synthesis of nitric oxide and catecholamines including dopamine and serotonin [14].
• The regulation of GTP cyclohydrolase I would lead to the regulation of tetrahydrobiopterin, an important cofactor for synthesis of neurotransmitters [2].
• The enzyme guanosine triphosphate cyclohydrolase (GTP cyclohydrolase), which in bacteria is known to be the first enzyme in the biosynthetic pathway for the synthesis of pteridines, has been discovered in extracts of Drosophila melanogaster [15].

Other interactions of Pu

• Late in embryogenesis, a Pu product is necessary for the proper pigmentation of larval cuticle and proper orientation and differentiation of other larval structures, particularly in the head region [7].
• Individuals heterozygous for the noncomplementing allele, Ddcn7, over the 12-band DDC deficiency, Df (2L)130, die at the end of embryogenesis as unhatched larvae with unpigmented mouth parts [16].
• At this stage the adult cuticle is unsclerotized and unpigmented and dopa decarboxylase levels, a key enzyme in catecholamine metabolism which provides the crosslinking agents as well as the precursors for melanin, is low [17].
• Functional interactions between GTP cyclohydrolase I and tyrosine hydroxylase in Drosophila [11].
• (1973) that zeste is the strucural locus for GTP cyclohydrolase [15].

Analytical, diagnostic and therapeutic context of Pu

• In order to examine the organization and function of this locus further, we have performed interallelic complementation tests on 25 Punch mutations, monitoring viability and enzyme activity in prepupae and adults [18].

References