Catecholamines up

Last updated
Catecholamines up
Identifiers
Organism Drosophila melanogaster (Fruit fly)
SymbolCatsup
Entrez 48805
HomoloGene 137786
RefSeq (mRNA) NM_080192
RefSeq (Prot) NP_524931
UniProt Q9V3A4
Search for
Structures Swiss-model
Domains InterPro

Catecholamines up (Catsup) is a dopamine regulatory membrane protein that functions as a zinc ion transmembrane transporter (orthologous to ZIP7), and a negative regulator of rate-limiting enzymes involved in dopamine synthesis and transport: Tyrosine hydroxylase (TH), GTP Cyclohydrolase I (GTPCH), and Vesicular Monoamine Transporter (VMAT) in Drosophila melanogaste r. [1] [2] [3] [4]

Contents

Catsup plays a significant role in zinc ion transmembrane transport, and the mutations in Catsup gene can lead to abnormal accumulation of membrane proteins, such as Notch, decreased Notch signalling, increase in levels of apoptosis, and induce of ER stress response. [4] Additionally, Catsup plays an important role in regulation of dopamine synthesis, and the mutations in Catsup gene can lead to hyperactivity of Catsup-regulated enzymes TH, GTPCH, and VMAT, as well as to increases in dopamine (DA) and tetrahydrobiopterin (BH4) levels. [1] [3]

Gene structure and function

Catsup is a pleiotropic quantitative trait gene that encodes a negative regulator of dopamine (DA) and tetrahydrobiopterin (BH4) synthesis, as well as synaptic vesicle uptake in Drosophila melanogaste r. [3] In dopamine synthesis, Catsup functions to inhibit Tyrosine hydroxylase (TH), GTP Cyclohydrolase I (GTPCH), and Vesicular Monoamine Transporter (VMAT) enzyme activity. [5] Various molecular polymorphisms of Catsup are associated with variations in quantitative traits, such as locomotor behavior, lifespan, and sensory bristle number. [3] Catsup protein is composed of seven transmembrane helices that induce post-translational modification of both enzymes TH and GTPCH, and two conserved extracellular ZIP Zinc transporter domains that possess zinc ion transmembrane transport activity. [3] [4] [6]

Catsup co-localizes with enzymes TH and VMAT to dopaminergic neuron cell bodies and synaptic termini. [3] Additionally, Catsup gene encodes Drosophila ortholog to ZIP7 zinc transporter protein, which is part of ZIP (Zrt/Irt-like protein) family in mammals. [4]

Role in regulation of dopamine biosynthesis

Catsup regulates production of dopamine by serving as a negative regulator of rate-limiting enzymes in dopamine and pteridine synthesis pathways, both of which are required to occur for production of dopamine. [6]

In dopamine synthesis pathway, Catsup negatively regulates Tyrosine hydroxylase (TH) activity, preventing TH catalyzed conversion of tyrosine to the precursor of dopamine, L-Dopa. [3]

In pteridine biosynthesis pathway, Catsup negatively regulates the activity of GTP Cyclohydrolase I (GTPCH), preventing GTPCH catalyzed biosynthesis of TH cofactor required for TH catalytic activity and regulation, tetrahydrobiopterin (BH4). [6]

Role in zinc ion transmembrane transport

Catsup gene encodes Drosophila ortholog to ZIP7 zinc transporter protein in mammals, which controls zinc homeostasis and maintains concentrations of free zinc low in cells. [4] Zinc transporters allow zinc transport into the cytoplasm of the cell, and disruptions to zinc transporters can lead to neurodevelopmental damages. [7]

Mutations

As the zinc ion transmembrane transporter, Catsup mutations can lead to abnormal accumulation of membrane proteins, such as Notch, decreased Notch signalling, increase in levels of apoptosis, and induce of ER stress response. [4]

As the regulator of dopamine biosynthesis, Catsup mutations can lead to hyperactivity of Catsup-regulated enzymes TH, GTPCH, and VMAT, as well as to increases in dopamine (DA) and tetrahydrobiopterin (BH4) levels. [1] [3]

Related Research Articles

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Phenylalanine hydroxylase</span> Mammalian protein found in Homo sapiens

Phenylalanine hydroxylase (PAH) (EC 1.14.16.1) is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin (BH4, a pteridine cofactor) and a non-heme iron for catalysis. During the reaction, molecular oxygen is heterolytically cleaved with sequential incorporation of one oxygen atom into BH4 and phenylalanine substrate. In humans, mutations in its encoding gene, PAH, can lead to the metabolic disorder phenylketonuria.

<span class="mw-page-title-main">Tetrahydrobiopterin</span> Chemical compound

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).

The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.

<span class="mw-page-title-main">Pterin</span> Chemical compound

Pterin is a heterocyclic compound composed of a pteridine ring system, with a "keto group" and an amino group on positions 4 and 2 respectively. It is structurally related to the parent bicyclic heterocycle called pteridine. Pterins, as a group, are compounds related to pterin with additional substituents. Pterin itself is of no biological significance.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter (DAT) also is a membrane-spanning protein coded for in the human by the SLC6A3 gene,, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

α-Methyl-<i>p</i>-tyrosine Chemical compound

α-Methyl-p-tyrosine (AMPT), or simply α-methyltyrosine, also known in its chiral 2-(S) form as metirosine, is a tyrosine hydroxylase enzyme inhibitor and is therefore a drug involved in inhibiting the catecholamine biosynthetic pathway. AMPT inhibits tyrosine hydroxylase whose enzymatic activity is normally regulated through the phosphorylation of different serine residues in regulatory domain sites. Catecholamine biosynthesis starts with dietary tyrosine, which is hydroxylated by tyrosine hydroxylase and it is hypothesized that AMPT competes with tyrosine at the tyrosine-binding site, causing inhibition of tyrosine hydroxylase.

<span class="mw-page-title-main">Tetrahydrobiopterin deficiency</span> Medical condition

Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing intellectual disability and other serious health problems. In healthy individuals, it is metabolised (hydroxylated) into tyrosine, another amino acid, by phenylalanine hydroxylase. However, this enzyme requires tetrahydrobiopterin as a cofactor and thus its deficiency slows phenylalanine metabolism.

<span class="mw-page-title-main">6-Pyruvoyltetrahydropterin synthase deficiency</span> Medical condition

6-Pyruvoyltetrahydropterin synthase deficiency is an autosomal recessive disorder that causes malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is a recessive disorder that is accompanied by hyperphenylalaninemia. Commonly reported symptoms are initial truncal hypotonia, subsequent appendicular hypertonia, bradykinesia, cogwheel rigidity, generalized dystonia, and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, oculogyric crises, somnolence, irritability, hyperthermia, and seizures. Chorea, athetosis, hypersalivation, rash with eczema, and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given folate antagonists such as methotrexate, which can interfere with a salvage pathway through which dihydrobiopterin is converted into tetrahydrobiopterin via dihydrofolate reductase. Treatment options include substitution with neurotransmitter precursors, monoamine oxidase inhibitors, and tetrahydrobiopterin. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype–phenotype correlation and outcome of these diseases, their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

<span class="mw-page-title-main">GTP cyclohydrolase I</span>

GTP cyclohydrolase I (GTPCH) (EC 3.5.4.16) is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH2-3'-TP).

<span class="mw-page-title-main">Tyrosine hydroxylase</span> Enzyme found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

<span class="mw-page-title-main">Tryptophan hydroxylase</span> Class of enzymes

Tryptophan hydroxylase (TPH) is an enzyme (EC 1.14.16.4) involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-dependent aromatic amino acid hydroxylases. TPH catalyzes the following chemical reaction

<span class="mw-page-title-main">Biopterin</span> Chemical compound

Biopterins are pterin derivatives which function as endogenous enzyme cofactors in many species of animals and in some bacteria and fungi. The prototypical compound of the class is biopterin, as shown in the infobox. Biopterins act as cofactors for aromatic amino acid hydroxylases (AAAH), which are involved in synthesizing a number of neurotransmitters including dopamine, norepinephrine, epinepherine, and serotonin, along with several trace amines. Nitric oxide synthesis also uses biopterin derivatives as cofactors. In humans, tetrahydrobiopterin (BH4) is the endogenous cofactor for AAAH enzymes.

Alkylglycerol monooxygenase (AGMO) is an enzyme that catalyzes the hydroxylation of alkylglycerols, a specific subclass of ether lipids. This enzyme was first described in 1964 as a pteridine-dependent ether lipid cleaving enzyme. In 2010 finally, the gene coding for alkylglycerol monooxygenase was discovered as transmembrane protein 195 (TMEM195) on chromosome 7. In analogy to the enzymes phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase and nitric oxide synthase, alkylglycerol monooxygenase critically depends on the cofactor tetrahydrobiopterin and iron.

<span class="mw-page-title-main">GCHFR</span> Protein-coding gene in the species Homo sapiens

GTP cyclohydrolase 1 feedback regulatory protein is an enzyme that in humans is encoded by the GCHFR gene.

Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years.

<span class="mw-page-title-main">Monooxygenase DBH-like 1</span> Protein-coding gene in the species Homo sapiens

DBH-like monooxygenase protein 1, also known as monooxygenase X, is an enzyme that in humans is encoded by the MOXD1 gene.

<span class="mw-page-title-main">Biopterin-dependent aromatic amino acid hydroxylase</span>

Biopterin-dependent aromatic amino acid hydroxylases (AAAH) are a family of aromatic amino acid hydroxylase enzymes which includes phenylalanine 4-hydroxylase, tyrosine 3-hydroxylase, and tryptophan 5-hydroxylase. These enzymes primarily hydroxylate the amino acids L-phenylalanine, L-tyrosine, and L-tryptophan, respectively.

The TH gene codes for the enzyme tyrosine hydroxylase.

Autosomal dominant GTP cyclohydrolase I deficiency (AD-GTPCHD) is a disease caused by dysfunction of GTP cyclohydrolase I, an enzyme that plays an important role in the synthesis of tetrahydrobiopterin, and, as a consequence, of dopamine. This condition is one of the six known causes of tetrahydrobiopterin deficiency and is the most frequently-reported cause of dopa-responsive dystonia.

References

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  2. O’Donnell, Janis M.; Stathakis, Dean G.; Burton, Denise; Chen, Zuomin (2002). Chemistry and Biology of Pteridines and Folates. Springer, Boston, MA. pp. 211–215. doi:10.1007/978-1-4615-0945-5_35. ISBN   9781461353171.
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  5. Carbone MA, Jordan KW, Lyman RF, Harbison ST, Leips J, Morgan TJ, DeLuca M, Awadalla P, Mackay TF (May 2006). "Phenotypic variation and natural selection at catsup, a pleiotropic quantitative trait gene in Drosophila". Current Biology. 16 (9): 912–9. doi: 10.1016/j.cub.2006.03.051 . PMC   10766118 . PMID   16682353.
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