Wikipedia

User:Calyvin/sandbox/Aromatic L-amino acid decarboxylase

Aromatic L amino acid decarboxylase (DOPA decarboxylase)
Ribbon diagram of a DOPA decarboxylase dimer.[1]
Identifiers
EC no.4.1.1.28
CAS no.9042-64-2
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
DOPA decarboxylase (aromatic L-amino acid decarboxylase)
Identifiers
SymbolDDC
NCBI gene1644
HGNC2719
OMIM107930
RefSeqNM_000790
UniProtP20711
Other data
EC number4.1.1.28
LocusChr. 7 p11
Search for
StructuresSwiss-model
DomainsInterPro

Aromatic L-amino acid decarboxylase (AADC or AAAD), also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme (EC 4.1.1.28).

Mechanism edit

The enzyme uses pyridoxal phosphate (PLP), the active form of vitamin B6, as a cofactor. PLP is essential to the mechanism of decarboxylation in AADC. In the active enzyme, PLP is bound to lysine-303 of AADC as a Schiff base. Upon substrate binding, lysine-303 is displaced by the substrate's amine. This positions the carboxylate of the substrate within the active site such that decarboxylation is favored. Decarboxylation of the substrate produces a quinonoid intermediate, which is subsequently protonated to produce a Schiff base adduct of PLP and the decarboxylated product. Lysine-303 can then regenerate the original Schiff base, releasing the product.[2]

 
Mechanism of aromatic L-amino acid decarboxylase

Structure edit

Aromatic L-amino acid decarboxylase is active as a homodimer. Before addition of the pyridoxal phosphate cofactor, the apoenzyme exists in an open conformation. Upon cofactor binding, a large structural transformation occurs as the subunits pull closer and close the active site. This conformational change results in the active, closed holoenzyeme.[3]

Regulation edit

AADC regulation, especially as it relates to L-DOPA decarboxylation, has been studied extensively. AADC has several conserved protein kinase A (PKA) and protein kinase G recognition sites, with residues S220, S336, S359, T320, and S429 all as potential phosphate acceptors. In vitro studies have confirmed PKA and PKG can both phosphorylate AADC, causing a significant increase in activity.[4][5] In addition, dopamine receptor antagonists have been shown to increase AADC activity in rodent models, while activation of some dopamine receptors suppresses AADC activity.[6] Such receptor mediated regulation is biphasic, with an initial short term activation followed by long term activation. The short term activation is thought to proceed through kinase activation and subsequent phosphorylation of AADC, while the sensitivity of long term activation to protein translation inhibitors suggests regulation of mRNA transcription.[7]

Reactions edit

AADC catalyzes several different decarboxylation reactions:[8]

However, some of these reactions do not seem to bear much or any biological significance. For example, histamine is biosynthesised strictly via the enzyme histidine decarboxylase in humans and other organisms.[9][10]

Biosynthetic pathways for catecholamines and trace amines in the human brain[11][12][13]
 
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid L-phenylalanine.
 
Human serotonin biosynthesis pathway

As a rate-limiting step edit

In normal dopamine and serotonin (5-HT) neurotransmitter synthesis, AADC is not the rate-limiting step in either reaction. However, AADC 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). AADC 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, AADC is also the rate-limiting enzyme in the formation of trace amines. Aromatic l-amino acid decarboxylase deficiency 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).[14] 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).[15]

Clinical Relevance edit

Genetics edit

The gene encoding the enzyme is referred to as DDC and located on chromosome 7 in humans.[16]

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[17] and autism. No direct correlation between gene variation and autism was found.[18]

More than 50 mutations of DDC have been correlated with AADC deficiency[19] This condition is most prevalent in Asia, presumably due to the founder effect.[20]

See also edit

References edit

  1. ^ 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". Nature Structural Biology. 8 (11): 963–7. doi:10.1038/nsb1101-963. PMID 11685243. S2CID 19160912.
  2. ^ Bertoldi M (March 2014). "Mammalian Dopa decarboxylase: structure, catalytic activity and inhibition". Archives of Biochemistry and Biophysics. 546: 1–7. doi:10.1016/j.abb.2013.12.020. PMID 24407024.
  3. ^ Giardina G, Montioli R, Gianni S, Cellini B, Paiardini A, Voltattorni CB, Cutruzzolà F (December 2011). "Open conformation of human DOPA decarboxylase reveals the mechanism of PLP addition to Group II decarboxylases". Proceedings of the National Academy of Sciences of the United States of America. 108 (51): 20514–9. doi:10.1073/pnas.1111456108. PMC 3251144. PMID 22143761.
  4. ^ Duchemin AM, Berry MD, Neff NH, Hadjiconstantinou M (August 2000). "Phosphorylation and activation of brain aromatic L-amino acid decarboxylase by cyclic AMP-dependent protein kinase". Journal of Neurochemistry. 75 (2): 725–31. doi:10.1046/j.1471-4159.2000.0750725.x. PMID 10899948.
  5. ^ Duchemin AM, Neff NH, Hadjiconstantinou M (July 2010). "Aromatic L-amino acid decarboxylase phosphorylation and activation by PKGIalpha in vitro". Journal of Neurochemistry. 114 (2): 542–52. doi:10.1111/j.1471-4159.2010.06784.x. PMID 20456015.
  6. ^ Hadjiconstantinou M, Neff NH (2008). "Enhancing aromatic L-amino acid decarboxylase activity: implications for L-DOPA treatment in Parkinson's disease". CNS Neuroscience & Therapeutics. 14 (4): 340–51. doi:10.1111/j.1755-5949.2008.00058.x. PMC 6494005. PMID 19040557.
  7. ^ Berry MD, Juorio AV, Li XM, Boulton AA (September 1996). "Aromatic L-amino acid decarboxylase: a neglected and misunderstood enzyme". Neurochemical Research. 21 (9): 1075–87. doi:10.1007/BF02532418. PMID 8897471.
  8. ^ "AADC". Human Metabolome database. Retrieved 17 February 2015.
  9. ^ Huang H, Li Y, Liang J, Finkelman FD (2018). "Molecular Regulation of Histamine Synthesis". Frontiers in Immunology. 9: 1392. doi:10.3389/fimmu.2018.01392. PMC 6019440. PMID 29973935.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Ichikawa A, Tanaka S (2012). Histamine Biosynthesis and Function. American Cancer Society. doi:10.1002/9780470015902.a0001404.pub2. ISBN 9780470015902. {{cite book}}: |work= ignored (help)
  11. ^ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
  12. ^ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375.
  13. ^ Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". European Journal of Pharmacology. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.
  14. ^ Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K, et al. (April 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. S2CID 12374358.
  15. ^ "Patient registry".
  16. ^ Scherer LJ, McPherson JD, Wasmuth JJ, Marsh JL (June 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.
  17. ^ Børglum AD, Bruun TG, Kjeldsen TE, Ewald H, Mors O, Kirov G, et al. (November 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.
  18. ^ 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. PMC 4826443. PMID 11992572.
  19. ^ Wassenberg, Tessa; Molero-Luis, Marta; Jeltsch, Kathrin; Hoffmann, Georg F.; Assmann, Birgit; Blau, Nenad; Garcia-Cazorla, Angeles; Artuch, Rafael; Pons, Roser; Pearson, Toni S.; Leuzzi, Vincenco (01 18, 2017). "Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency". Orphanet Journal of Rare Diseases. 12 (1): 12. doi:10.1186/s13023-016-0522-z. ISSN 1750-1172. PMC 5241937. PMID 28100251. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  20. ^ Lee, Hsiu-Fen; Tsai, Chi-Ren; Chi, Ching-Shiang; Chang, Tung-Ming; Lee, Huei-Jane (2009-03). "Aromatic L-amino acid decarboxylase deficiency in Taiwan". European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society. 13 (2): 135–140. doi:10.1016/j.ejpn.2008.03.008. ISSN 1532-2130. PMID 18567514. {{cite journal}}: Check date values in: |date= (help)

External links edit

Category:EC 4.1.1

Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Calyvin/sandbox/Aromatic_L-amino_acid_decarboxylase&oldid=1145322519"