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Information on EC 1.1.99.1 - choline dehydrogenase and Organism(s) Homo sapiens
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1.1.99.1 choline dehydrogenaseIUBMB Comments
A quinoprotein. In many bacteria, plants and animals, the osmoprotectant betaine is synthesized using different enzymes to catalyse the conversion of (1) choline into betaine aldehyde and (2) betaine aldehyde into betaine. In plants, the first reaction is catalysed by EC 1.14.15.7, choline monooxygenase, whereas in animals and many bacteria, it is catalysed by either membrane-bound choline dehydrogenase (EC 1.1.99.1) or soluble choline oxidase (EC 1.1.3.17) . The enzyme involved in the second step, EC 1.2.1.8, betaine-aldehyde dehydrogenase, appears to be the same in plants, animals and bacteria.
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The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
choline dehydrogenase, chdh, chodh, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CHD
CHDH
choline oxidase
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choline-cytochrome c reductase
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choline:(acceptor) oxidoreductase
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dehydrogenase, choline
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oxidase, choline
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CHD
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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redox reaction
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reduction
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
choline:acceptor 1-oxidoreductase
A quinoprotein. In many bacteria, plants and animals, the osmoprotectant betaine is synthesized using different enzymes to catalyse the conversion of (1) choline into betaine aldehyde and (2) betaine aldehyde into betaine. In plants, the first reaction is catalysed by EC 1.14.15.7, choline monooxygenase, whereas in animals and many bacteria, it is catalysed by either membrane-bound choline dehydrogenase (EC 1.1.99.1) or soluble choline oxidase (EC 1.1.3.17) [4]. The enzyme involved in the second step, EC 1.2.1.8, betaine-aldehyde dehydrogenase, appears to be the same in plants, animals and bacteria.
CAS REGISTRY NUMBER
COMMENTARY
9028-67-5
identical with CAS Reg. No. of EC 1.1.3.17
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
choline + acceptor
betaine aldehyde + reduced acceptor
relation of plasma choline and betaine to cardiovascular risk factors, mitochondrial choline dehydrogenase pathway
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
the enzyme has 3 functional domains, named FAD/NAD(P)-binding domain 1 (FB1, residues 39 to 326), FAD-linked reductase domain (RD, residues 333 to 515) and FAD/NAD(P)-binding domain 2 (FB2, residues 511 to 574)
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
population-based study, unfavorable cardiovascular risk factor profile associated with high choline and low betaine concentrations, choline and betaine associated in opposite directions with key components of metabolic syndrome, disruption of mitochondrial choline dehydrogenase pathway
additional information
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population-based study, unfavorable cardiovascular risk factor profile associated with high choline and low betaine concentrations, choline and betaine associated in opposite directions with key components of metabolic syndrome, disruption of mitochondrial choline dehydrogenase pathway
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
CHD is predominantly active in the two main detoxifying organs liver and kidney
additional information
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CHD is predominantly active in the two main detoxifying organs liver and kidney
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
a nuclear-encoded, membrane-located, mitochondrial enzyme. Human CHD is not an integral membrane protein, but associated to the membrane
CHDH appears to have a mitochondria-targeting sequence at its N-terminus (residues 1 to 38). CHDH is found on both the outer and inner membranes of mitochondria in resting cells. Upon induction of mitophagy, CHDH accumulates on the outer membrane in a mitochondrial potential-dependent manner. CHDH accumulates on the outer membrane following mitochondrial damage. Topology of CHDH in the mitochondrial membrane and mechanism by which CHDH translocates across the mitochondrial membranes, overview
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
the enzyme belongs to the glucose-methanol-choline (GMC) enzyme oxidoreductase enzyme superfamily, members of the family contain a glycine box. Other members of the family all use FAD as cofactor, overall structures and active sites of members of the GMC oxidoreductase enzyme superfamily, overview
malfunction
physiological function
additional information
malfunction
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mutant sperm produced by men who are show polymorphisms rs12676 have 40% and 73% lower ATP concentrations, respectively, in their sperm than controls. Variation rs12676 is associated with decreased CHDH protein in sperm and hepatocytes. A second single-nucleotide polymorphism located in the coding region of IL17BR, rs1025689, is linked to altered sperm motility characteristics and changes in choline metabolite concentrations in sperm
malfunction
knockdown of CHDH expression impairs CCCP-induced mitophagy and PARK2/parkin-mediated clearance of mitochondria in mammalian cells, including HeLa cells. Conversely, overexpression of CHDH accelerates PARK2-mediated mitophagy
malfunction
the enzyme is associated with male infertility. Absence of CHD enzyme activity causes diminished sperm motility, and mitochondrial alterations are described in testis as well as liver, kidney and heart. Impairments in human CHD activity are associated with homocysteinuria, an accumulation of homocysteine that represents an independent risk factor for cardiovascular diseases. It exists a correlation between high concentrations of choline, low concentrations of glycine betaine in blood and a high-risk profile for cardiovascular disease. Choline deficiency the brain may degrade the membrane phospholipids of the neurons in order to recycle choline for the production of acetylcholine. Localization of Leu78 is relevant to the polymorphism rs12676 associated with male infertility and increased risk factor for breast cancer, on the surface of the enzyme
physiological function
pivotal role of CHDH in mitophagy. CHDH is required for mitophagy in which CHDH interacts with SQSTM1, a mitophagic adaptor molecule, and subsequently facilitates the recruitment of MAP1LC3B/LC3B (LC3) into the mitochondria. CHDH is not a substrate of PARK2 but interacts with SQSTM1 independently of PARK2 to recruit SQSTM1 into depolarized mitochondria. The FB1 domain of CHDH is exposed to the cytosol and is required for the interaction with SQSTM1, and overexpression of the FB1 domain only in cytosol reduces CCCP-induced mitochondrial degradation via competitive interaction with SQSTM1. CHDH is required for PARK2-mediated mitophagy for the recruitment of SQSTM1 and LC3 onto the mitochondria for cargo recognition. CHDH overexpression enhances CCCP-induced clearance of mitochondria. But the expression level of CHDH does not affect the stability of PINK1 protein, although CCCP treatment stabilizes PINK1 in mitochondria. Mitophagic activity of CHDH is independent of CDH enzyme activity
physiological function
the enzyme oxidizes choline. The regulation of the concentration of choline in tissues and blood is very important as choline plays key roles in different pathways. Choline is involved in the epigenetic regulation of gene expression through DNA methylation, in the biosynthesis of lipoproteins and membrane phospholipids and in the biosynthesis of the neurotransmitter acetylcholine. It is therefore important for the integrity of cell membranes, lipid metabolism and nerve function. Choline is considered an important nutrient for fetal and brain development, and choline is a constituent of phospholipids involved in signal transduction, such as phosphatidylcholine and plasmalogen, and of the phospholipid platelet activating factor. The metabolism of choline is also interrelated with the metabolism of folate. CHD is important for the catabolic utilization of choline when the latter is administered as a pharmacological agent, because choline is involved in the stimulation of cholinergic neuronal activity and in restoring phosphatidylcholine levels in the neuronal membrane, thus displaying a neuroprotective action relevant for diseases such as memory and cognitive deficits. CHD, predominantly active in the two main detoxifying organs liver and kidney, determines the half-life of choline in blood. The metabolic oxidation of choline is related to the risk of developing breast cancer
additional information
CHDH appears to have a mitochondria-targeting sequence at its N-terminus (residues 1 to 38) and 3 functional domains, named FAD/NAD(P)-binding domain 1 (FB1, residues 39 to 326), FAD-linked reductase domain (RD, residues 333 to 515) and FAD/NAD(P)-binding domain 2 (FB2, residues 511 to 574)
additional information
rapid turnover of choline when administered as a drug, about 50% of injected choline are directly eliminated via liver and kidney. Structure homology modeling
additional information
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rapid turnover of choline when administered as a drug, about 50% of injected choline are directly eliminated via liver and kidney. Structure homology modeling
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CHDH_HUMAN
594
0
65358
Swiss-Prot
Mitochondrion (Reliability: 1)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G233T
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naturally occuring mutation, identificatin of polymorphism rs12676, a non-synonymous SNP located in the CHDH coding region, which is associated with altered sperm motility patterns and dysmorphic mitochondrial structure in sperm, and is associated with increased susceptibility to dietary choline deficiency and risk of breast cancer, phenotye, overview
L78X
localization of Leu78, which is relevant to the polymorphism rs12676 associated with male infertility and increased risk factor for breast cancer, on the surface of the enzyme. Such a replacement of a hydrophobic residue with a positively charge one would locally alter the polarity of the enzyme surface, perhaps decreasing the stability of the enzyme
additional information
construction of a series of CHDH deletion mutants in HeLa cells. Overexpression of the CHDH-RDDELTA or CHDHFB2DELTA mutants induces colocalization of GFP-LC3 with Mito-RFP as effectively as wild-type CHDH, but the CHDH-FB1DELTA mutant fails to do so. Knockdown of CHDH expression impairs CCCP-induced mitophagy and PARK2/parkin-mediated clearance of mitochondria in mammalian cells, including HeLa cells. Conversely, overexpression of CHDH accelerates PARK2-mediated mitophagy. Overexpression of the FB1 domain only in cytosol reduces CCCP-induced mitochondrial degradation via competitive interaction with SQSTM1
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
high instability of the enzyme once it is removed from the inner mitochondrial membrane
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene Chdh, DNA and amino acid sequence determination and analysis, polymorphism rs12676 genotyping, overview
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gene CHDH, recombinant expression of wild-type and truncated mutant enzymes, enzyme overexpression in HeLa cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
study of prognostic biomarkers for breast cancer identifies the expression of CHD among three human genes controlled by estrogens, and shows that this is a strong predictor of the outcome of treatment with tamoxifen in early-stage (ER)-positive breast cancer patients
medicine
population-based study, relation of plasma choline and betaine to smoking, physical activity, BMI, percent body fat, waist circumference, blood pressure, serum lipids and glucose
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Konstantinova, S.V.; Tell, G.S.; Vollset, S.E.; Nygard, O.; Bleie, O.; Ueland, P.M.
Divergent associations of plasma choline and betaine with components of metabolic syndrome in middle age and elderly men and women
J. Nutr.
138
914-920
2008
Homo sapiens (Q8NE62), Homo sapiens
Johnson, A.R.; Lao, S.; Wang, T.; Galanko, J.A.; Zeisel, S.H.
Choline dehydrogenase polymorphism rs12676 is a functional variation and is associated with changes in human sperm cell function
PLoS ONE
7
e36047
2012
Homo sapiens
Salvi, F.; Gadda, G.
Human choline dehydrogenase medical promises and biochemical challenges
Arch. Biochem. Biophys.
537
243-252
2013
Homo sapiens (Q8NE62), Homo sapiens, Rattus norvegicus (Q6UPE0)
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Release 2023.1 (January 2023)
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