Aromatic L-amino acid decarboxylase

aromatic-L-amino-acid decarboxylase

Ribbon diagram of a DOPA decarboxylase dimer.[1]
Identifiers
EC number 4.1.1.28
CAS number 9042-64-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
DOPA decarboxylase (aromatic L-amino acid decarboxylase)
Identifiers
Symbol DDC
Entrez 1644
HUGO 2719
OMIM 107930
RefSeq NM_000790
UniProt P20711
Other data
EC number 4.1.1.28
Locus Chr. 7 p11

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]

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
The image above contains clickable links
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. Deficiency of AAAD is associated with various symptoms as severe developmental delay, oculogyric crises and autonomic dysfunction. The molecular and clinical spectrum of AAAC deficiency is heterogeneous. The first case of AADC deficiency was described in twin brothers 1990. Patients can be treated with dopamine agonists, MAO inhibitors, and pyridoxine (vitamin B6).[6] Clinical phenotype and response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).[7]

Genetics

The gene encoding the enzyme is referred to as DDC and located on chromosome 7 in humans.[8] 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[9] and autism. No direct correlation between gene variation and autism was found.[10]

See also

References

  1. ↑ PDB: 1JS3​; Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Malashkevich VN (Nov 2001). "Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase". Nature Structural Biology 8 (11): 963–7. doi:10.1038/nsb1101-963. PMID 11685243.
  2. ↑ Logan CM, Rice MK (1987). Logan's Medical and Scientific Abbreviations. Philadelphia: J. B. Lippincott Company. p. 3. ISBN 0-397-54589-4.
  3. ↑ "AADC". Human Metabolome database. Retrieved 17 February 2015.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K, Sharma R, De Vivo DC (Apr 2004). "Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis". Neurology 62 (7): 1058–65. doi:10.1212/WNL.62.7.1058. PMID 15079002.
  7. ↑ "Patient registry".
  8. ↑ Scherer LJ, McPherson JD, Wasmuth JJ, Marsh JL (Jun 1992). "Human dopa decarboxylase: localization to human chromosome 7p11 and characterization of hepatic cDNAs". Genomics 13 (2): 469–71. doi:10.1016/0888-7543(92)90275-W. PMID 1612608.
  9. ↑ Børglum AD, Bruun TG, Kjeldsen TE, Ewald H, Mors O, Kirov G, Russ C, Freeman B, Collier DA, Kruse TA (Nov 1999). "Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder". Molecular Psychiatry 4 (6): 545–51. doi:10.1038/sj.mp.4000559. PMID 10578236.
  10. ↑ Lauritsen MB, Børglum AD, Betancur C, Philippe A, Kruse TA, Leboyer M, Ewald H (May 2002). "Investigation of two variants in the DOPA decarboxylase gene in patients with autism". American Journal of Medical Genetics 114 (4): 466–70. doi:10.1002/ajmg.10379. PMID 11992572.

External links

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