Actions

Biochemistry::Dopamine

::concepts

Dopamine::journal    Title::pages    Vauthors::volume    Dopamine::issue    Brain::drugs    System::reward

Biochemistry

Synthesis

Diagram showing L-DOPA and dopamine molecular structures, with the reaction that connects them.
The reaction from L-DOPA to dopamine

Dopamine is synthesized in a restricted set of cell types, mainly neurons and cells in the medulla of the adrenal glands.<ref name=Seeman/> The metabolic pathway is:

L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine

The direct precursor of dopamine, L-DOPA, can be synthesized indirectly from the essential amino acid phenylalanine or directly from the non-essential amino acid tyrosine.<ref name=Musacchio/> These amino acids are found in nearly every protein and, as such, are provided by ingestion of protein-containing food, with tyrosine being the most common. Although dopamine is also found in many types of food, it is incapable of crossing the blood–brain barrier that surrounds and protects the brain.<ref name="Nice-pharma"/> It must therefore be synthesized inside the brain to perform its neural actions.<ref name="Nice-pharma"/>

L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine hydroxylase (PAH), with molecular oxygen (O2) and tetrahydrobiopterin (THB) as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase (TH), with tetrahydrobiopterin (THB), O2, and probably ferrous iron (Fe2+) as cofactors.<ref name=Musacchio>{{#invoke:citation/CS1|citation |CitationClass=book }}</ref> L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC; also known as DOPA decarboxylase (DDC)), with pyridoxal phosphate (PLP) as the cofactor.<ref name=Musacchio/>

Dopamine itself is used as precursor in the synthesis of the neurotransmitter norepinephrine and the hormone epinephrine.<ref name=Musacchio/> Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase (DBH), with O2 and L-ascorbic acid as cofactors.<ref name=Musacchio/> Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-methionine (SAM) as the cofactor.<ref name=Musacchio/>

Some of the cofactors also require their own synthesis.<ref name=Musacchio/> Deficiency in any required amino acid or cofactor can impair the synthesis of dopamine, norepinephrine, and epinephrine.<ref name=Musacchio/>

Degradation

Diagram of primary pathways of dopamine metabolism. The metabolism of dopamine into DOPAC (3,4-dihydroxyphenylacetic acid) and 3-MT (3-methoxytyramine) is followed by metabolism of these intermediate products into HVA (homovanillic acid) by the action of MAO (monoamine oxidase) and COMT (catechol-O-methyltransferase).
Primary pathways for dopamine metabolism
MAO: Monoamine oxidase
COMT: catechol-O-methyltransferase
HVA: Homovanillic acid

Dopamine is broken down into inactive metabolites by a set of enzymes, monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), acting in sequence.<ref name=Eisenhofer>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> Both isoforms of monoamine oxidase, MAO-A and MAO-B, are effective.<ref name=Musacchio/> A variety of breakdown pathways are possible, but regardless of which pathway is followed, the primary final product is homovanillic acid, which has no known biological activity.<ref name=Eisenhofer/> From the bloodstream, homovanillic acid is filtered out by the kidneys and then excreted in the urine.<ref name=Eisenhofer/> Homovanillic acid levels in the bloodstream have sometimes been used as a measure of brain dopamine activity, but the validity of this approach has been questioned due to the difficulty of compensating for peripheral dopamine metabolism.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Although dopamine is normally broken down by oxidation catalyzed by enzymes, it is also susceptible to autoxidation—that is, direct reaction with oxygen, yielding quinones plus various free radicals as products.<ref name=Sulzer>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> The rate of autoxidation can be increased by the presence of ferrous iron or other factors. The ability of dopamine autoxidation to produce quinones and free radicals makes it a potent cell toxin, and there is evidence that this mechanism may contribute to the cell loss that occurs in Parkinson's disease and other conditions.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>


Dopamine sections
Intro  Structure  Biochemistry  Functions  Medical uses  Pharmacology  Diseases and disorders  Comparative biology and evolution  History and development  See also   References   

Biochemistry
PREVIOUS: StructureNEXT: Functions
<<>>