Aromatic L-amino acid decarboxylase

Aromatic L-amino acid decarboxylase (EC 4.1.1.28, synonyms: DOPA decarboxylase, tryptophan decarboxylase, 5-hydroxytryptophan decarboxylase, AAAD,^[2] AADC) is a lyase enzyme.

Reactions

It catalyzes several different decarboxylation reactions:^[3]

L-DOPA to dopamine - a neurotransmitter
5-HTP to serotonin (5-HT) - a neurotransmitter
L-histidine to histamine - a neurotransmitter
phenylalanine to phenethylamine - trace amine neurotransmitter
L-tyrosine to tyramine - trace amine neurotransmitter
tryptophan to tryptamine - trace amine neurotransmitter

The enzyme uses pyridoxal phosphate, the active form of vitamin B6, as a cofactor.

Human biosynthesis pathway for trace amines and catecholamines^[4]^[5]

Graphic of trace amine and catecholamine metabolism

N-Methylphenethylamine

AADC

In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine.

Human serotonin biosynthesis pathway

As a rate-limiting step

In normal dopamine and serotonin (5-HT) neurotransmitter synthesis, AAAD is not the rate-limiting step in either reaction. However, AAAD becomes the rate-limiting step of dopamine synthesis in patients treated with L-DOPA (such as in Parkinson's Disease), and the rate-limiting step of serotonin synthesis in people treated with 5-HTP (such as in mild depression or dysthymia). AAAD is inhibited by Carbidopa outside of the blood brain barrier to inhibit the premature conversion of L-DOPA to Dopamine in the treatment of Parkinson's.

In humans, AAAD is also the rate-limiting enzyme in the formation of trace amine neurotransmitters.

Genetics

The gene encoding the enzyme is referred to as DDC and located on chromosome 7 in humans.^[6] Single nucleotide polymorphisms and other gene variations have been investigated in relation to neuropsychiatric disorders, e.g., a one-base pair deletion at –601 and a four-base pair deletion at 722–725 in exon 1 in relation to bipolar disorder^[7] and autism. No direct correlation between gene variation and autism was found.^[8]

References

↑ PDB: 1JS3; Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Malashkevich VN (November 2001). "Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase". Nat. Struct. Biol. 8 (11): 963–7. doi:10.1038/nsb1101-963. PMID 11685243.
↑ Logan, Carolynn M.; Rice, M. Katherine (1987). Logan's Medical and Scientific Abbreviations. Philadelphia: J. B. Lippincott Company. p. 3. ISBN 0-397-54589-4.
↑ "AADC". Human Metabolome database. Retrieved 17 February 2015.
↑ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
↑ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375.
↑ Lisa J. Scherer, John D. McPherson, John J. Wasmuth and J. Lawrence Marsh (June 1992). "Human dopa decarboxylase: Localization to human chromosome 7p11 and characterization of hepatic cDNAs". Genomics 13 (2): 469–471. doi:10.1016/0888-7543(92)90275-W. PMID 1612608.
↑ A. D. Borglum, T. G. Bruun, T. E. Kjeldsen, H. Ewald, O. Mors, G. Kirov, C. Russ, B. Freeman, D. A. Collier & T. A. Kruse (November 1999). "Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder". Molecular Psychiatry 4 (6): 545–541. doi:10.1038/sj.mp.4000559. PMID 10578236.
↑ Marlene B. Lauritsen, Anders D. Borglum, Catalina Betancur, Anne Philippe, Torben A. Kruse, Marion Leboyer & Henrik Ewald (May 2002). "Investigation of two variants in the DOPA decarboxylase gene in patients with autism". American Journal of Medical Genetics 114 (4): 466–460. doi:10.1002/ajmg.10379. PMID 11992572.

External links

Aromatic-L-Amino-Acid Decarboxylases at the US National Library of Medicine Medical Subject Headings (MeSH)

Enzymes involved in neutrotransmission

monoamine

histidine → histamine

anabolism:	Histidine decarboxylase

catabolism:	Histamine N-methyltransferase Diamine oxidase

tyrosine→dopamine→epinephrine

anabolism:	Tyrosine hydroxylase Aromatic L-amino acid decarboxylase Dopamine beta-hydroxylase Phenylethanolamine N-methyltransferase

catabolism:	Catechol-O-methyl transferase Monoamine oxidase

glutamate→GABA

anabolism:	Glutamate decarboxylase

catabolism:	4-aminobutyrate transaminase

tryptophan→serotonin→melatonin

arginine→NO

Nitric oxide synthase (NOS1, NOS2, NOS3)

choline→Acetylcholine

anabolism:	Choline acetyltransferase

catabolism:	Cholinesterase (Acetylcholinesterase, Butyrylcholinesterase)

Carbon-carbon lyases (EC 4.1)

4.1.1: Carboxy-lyases	Acetoacetate decarboxylase Adenosylmethionine decarboxylase Aromatic L-amino acid decarboxylase Glutamate decarboxylase Histidine decarboxylase Lysine decarboxylase Malonyl-CoA decarboxylase Ornithine decarboxylase Oxaloacetate decarboxylase Phosphoenolpyruvate carboxykinase Phosphoenolpyruvate carboxylase Phosphoribosylaminoimidazole carboxylase Pyrophosphomevalonate decarboxylase Pyruvate decarboxylase RuBisCO Uridine monophosphate synthetase/Orotidine 5'-phosphate decarboxylase Uroporphyrinogen III decarboxylase

4.1.2: Aldehyde-lyases	Fructose-bisphosphate aldolase Aldolase A Aldolase B Aldolase C 2-hydroxyphytanoyl-CoA lyase Threonine aldolase

4.1.3: Oxo-acid-lyases	Isocitrate lyase 3-hydroxy-3-methylglutaryl-CoA lyase

4.1.99: Other	Tryptophanase

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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