Literature summary for 1.14.17.1 extracted from

Vendelboe, T.V.; Harris, P.; Zhao, Y.; Walter, T.S.; Harlos, K.; El Omari, K.; Christensen, H.E.
The crystal structure of human dopamine beta-hydroxylase at 2.9 A resolution (2016), Sci. Adv., 2, e1500980 .

Search for more literature for 1.14.17.1

Application

Application	Comment	Organism
drug development	inhibitors of enzyme DBH nepicastat and etamicastat are currently in clinical development for treatment of cocaine dependence	Homo sapiens
medicine	inhibitors of enzyme DBH nepicastat and etamicastat are currently in clinical development for treatment of cocaine dependence	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant expression in HEK 293S cells	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
etamicastat	-	Homo sapiens
nepicastat	-	Homo sapiens

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Cu2+	DBH is an ascorbate-dependent glycoprotein that requires two type 2 bound copper ions per subunit to be active. copper sites are labile and termed CuH and CuM, respectively. CuH is coordinated to three histidines and CuM to two histidines and a methionine. CuM is involved in dioxygen binding and is the site for substrate hydroxylation, and CuH is the site of electron transfer	Homo sapiens
additional information	the structure of the common DOMON (dopamine beta-monooxygenase N-terminal) domain reveals a possible metal-binding site and a ligand-binding pocket, coordinating residues are Asp99, Leu100, Ala115, and Asp130	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
dopamine + ascorbate + O2	Homo sapiens	-	noradrenaline + dehydroascorbate + H2O	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P09172	-	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
glycoprotein	DBH is an ascorbate-dependent glycoprotein, glycosylation is observed at all four predicted sites: Asn64, Asn184, Asn344, and Asn566	Homo sapiens

Reaction

Reaction	Comment	Organism	Reaction ID
dopamine + 2 ascorbate + O2 = noradrenaline + 2 monodehydroascorbate + H2O	during the reaction, an O atom from molecular O2 is inserted at the beta-carbon in dopamine with retention of configuration, and the second O atom goes to water. The reaction also requires two electrons provided by two ascorbate molecules that are oxidized to semihydroascorbate	Homo sapiens	a

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
dopamine + ascorbate + O2	-	Homo sapiens	noradrenaline + dehydroascorbate + H2O	-	?

Subunits

Subunits	Comment	Organism
dimer or tetramer	the enzyme occurs borh as dimer and tetramer, which can be separated by size exclusion chromatography. The dimer and tetramer do not interconvert in the pH interval pH 4-9. Under denaturing conditions, the tetramer converts to a dimer, and upon addition of a reducing agent, the dimer converts to a monomer. The dimeric structure is asymmetric. In the A chain, the two catalytic CuH and CuM domains are in a closed conformation, and in the B chain, they adopt the same open conformation as seen in peptidylglycine alpha-hydroxylating (and alpha-amidating) monooxygenase (PHM), the catalytic CuH domain in chain A is moved away from the DOMON domain and closer to the catalytic CuM domain. The DOMON domain has an immunoglobulin (Ig)like beta-sandwich structure, the catalytic core (the CuH and CuM domains) has the same topology as the structure of PHM, and the dimerization domains consisting of two antiparallel alpha helices form a four-helix bundle. Following the dimerization domain, there is a beta-strand (residues 561 to 566) taking part in the catalytic CuM domain and a beta-strand (residues 608 to 614) that is part of the DOMON domain, creating a very integrated structure, coordinating residues are Asp99, Leu100, Ala115, and Asp130. The DOMON domain and the dimerization domain are linked via C154-C596. Chain A is linked via two intermolecular disulfide bonds with chain B in the dimerization domain. Enzyme structure analysis, detailed overview	Homo sapiens

Synonyms

Synonyms	Comment	Organism
DBH	-	Homo sapiens
dopamine beta-hydroxylase	-	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
ascorbate	DBH is an ascorbate-dependent glycoprotein that requires two type 2 bound copper ions per subunit to be active	Homo sapiens

General Information

General Information	Comment	Organism
evolution	DBH is a member of a small unique class of copper-containing hydroxylases that are found in eukaryotes, and all play a critical role in the biosynthesis of neurotransmitters and hormones. The other members of the family are the bifunctional enzyme peptidylglycine alpha-hydroxylating (and alpha-amidating) monooxygenase (PHM), monooxygenase X (DBH-like monooxygenase protein 1, MOXD1), and tyramine beta-monooxygease (TBH), which is the insect homologue of DBH	Homo sapiens
additional information	enzyme structure analysis, detailed overview	Homo sapiens
physiological function	dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine in the biosynthesis of catecholamines	Homo sapiens

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Release 2023.1 (January 2023)