Catecholamines up (Catsup) is a

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

regulatory

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

that functions as a zinc ion transmembrane transporter (

orthologous Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

to ZIP7), and a negative regulator of rate-limiting enzymes involved in

synthesis and transport:

Tyrosine hydroxylase 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 t ...

(TH),

GTP Cyclohydrolase I GTP cyclohydrolase I (GTPCH) () 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-dihydroneop ...

(GTPCH), and

Vesicular Monoamine Transporter 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, ...

(VMAT) in '' Drosophila melanogaste''r. 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

, and induce of ER stress response. Additionally, Catsup plays an important role in regulation of

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

(DA) and

tetrahydrobiopterin 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 serotoni ...

(BH₄) levels.

Gene structure and function

Catsup is a

pleiotropic Pleiotropy (from Greek , 'more', and , 'way') occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic g ...

quantitative trait gene that encodes a negative regulator of

(DA) and

(BH₄) synthesis, as well as synaptic vesicle uptake in '' Drosophila melanogaste''r. In dopamine synthesis, Catsup functions to inhibit

(TH),

(GTPCH), and

(VMAT) enzyme activity. Various molecular polymorphisms of Catsup are associated with variations in quantitative traits, such as locomotor behavior, lifespan, and sensory bristle number. 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. Catsup co-localizes with enzymes TH and VMAT to dopaminergic neuron cell bodies and synaptic termini. Additionally, Catsup gene encodes ''

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...

'' ortholog to ZIP7

zinc transporter protein Zinc transporter proteins (Zrt), or simply zinc transporters, are membrane transport proteins of the solute carrier family which control the membrane transport of zinc and regulate its intracellular and cytoplasmic concentrations. They include two ...

, which is part of ZIP (Zrt/Irt-like protein) family in mammals.

Role in regulation of dopamine biosynthesis

Catsup regulates production of

by serving as a negative regulator of rate-limiting enzymes in

and

pteridine Pteridine is an aromatic chemical compound composed of fused pyrimidine and pyrazine rings. A pteridine is also a group of heterocyclic compounds containing a wide variety of substitutions on this structure. Pterins and flavins are classes of su ...

synthesis pathways, both of which are required to occur for production of

. In dopamine synthesis pathway, Catsup negatively regulates

(TH) activity, preventing TH catalyzed conversion of

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

to the precursor of dopamine,

L-Dopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

. In

biosynthesis pathway, Catsup negatively regulates the activity of

(GTPCH), preventing GTPCH catalyzed biosynthesis of TH cofactor required for TH catalytic activity and regulation,

(BH4).

Role in zinc ion transmembrane transport

Catsup gene encodes ''

'' ortholog to ZIP7

in mammals, which controls zinc homeostasis and maintains concentrations of free zinc low in cells. Zinc transporters allow zinc transport into the cytoplasm of the cell, and disruptions to zinc transporters can lead to neurodevelopmental damages.{{cite journal , vauthors = Jeong J, Eide DJ , title = The SLC39 family of zinc transporters , journal = Molecular Aspects of Medicine , volume = 34 , issue = 2–3 , pages = 612–9 , pmid = 23506894 , pmc = 3602797 , doi = 10.1016/j.mam.2012.05.011 , year = 2013

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. 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

(DA) and

(BH₄) levels.

References

Transmembrane transporters