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Literature summary extracted from

  • Sanchez-Jimenez, F.; Pino-Angeles, A.; Rodriguez-Lopez, R.; Morales, M.; Urdiales, J.L.
    Structural and functional analogies and differences between histidine decarboxylase and aromatic l-amino acid decarboxylase molecular networks biomedical implications (2016), Pharmacol. Res., 114, 90-102 .
    View publication on PubMed

Cloned(Commentary)

EC Number Cloned (Comment) Organism
4.1.1.22 gene hdc, located on chromosome 15q21.2, different splicing products, sequence comparisons, regulatory cis elements in the human HDC promoter (TATA, GC, CACC, Sp1 and GATA boxes): two cis-elements are located between the positions -855 and -821 with respect to the transcription start point that regulates the transcription of the HDC in human basophilic cells. Other regulatory elements are located in position -500 and between positions -532 and -497. The HDC promoter also contains a CpG island involved in epigenetic regulation of its expression during the differentiation of histamine-producing cells Homo sapiens
4.1.1.28 gene ddc, located on chromosome 7p12.2, sequence comparisons, in addition to a TATA box, a strong promoter is detectedin the human DDC gene. It contains three positive regulatory elements located from position -560 bp to -1. Another two negative regulatory cis-elements are detected in between -9000 and 560 and 396-31. An alternative-promoter mechanism for regulating tissue-specific expression of DDC gene is observed Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
4.1.1.22 additional information the mutation of a stop codon after W317 in gene hdc leads to a truncated enzyme and the Tourette syndrome Homo sapiens
4.1.1.28 A275T naturally occuring mutation involved in aromatic-L-amino-acid decarboxylase deficiency Homo sapiens
4.1.1.28 A91V naturally occuring mutation involved in aromatic-L-amino-acid decarboxylase deficiency Homo sapiens
4.1.1.28 F309L naturally occuring mutation, involved in aromatic-L-amino-acid decarboxylase deficiency Homo sapiens
4.1.1.28 G102S naturally occuring mutation, involved in aromatic-L-amino-acid decarboxylase deficiency Homo sapiens
4.1.1.28 R347Q naturally occuring mutation involved in aromatic-L-amino-acid decarboxylase deficiency Homo sapiens
4.1.1.28 S147R naturally occuring mutation, involved in aromatic-L-amino-acid decarboxylase deficiency Homo sapiens
4.1.1.28 S250F naturally occuring mutation, involved in aromatic-L-amino-acid decarboxylase deficiency Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
4.1.1.22 4(5)-aminooxymethylimidazole O-IMHA, a substrate analogue Homo sapiens
4.1.1.22 alpha-Fluoromethylhistidine
-
Homo sapiens
4.1.1.22 epigallocatechin-3-gallate EGCG, the inhibitory effect is mediated by blocking the entrance to the catalytic site, therefore, preventing substrate binding Homo sapiens
4.1.1.22 methyl L-histidinate the compound is able to block the reaction at the Michaelis complex step in HDC Homo sapiens
4.1.1.22 additional information successful strategies to inhibit the decarboxylase have included the synthesis of fluoro-derivatives, which act as competitive and/or suicide inhibitors, as it is the case of alpha-fluoromethylhistidine Homo sapiens
4.1.1.28 carbidopa the compound is able to block the reaction at the Michaelis complex step in DDC Homo sapiens
4.1.1.28 epigallocatechin-3-gallate EGCG, the inhibitory effect is mediated by blocking the entrance to the catalytic site, therefore, preventing substrate binding Homo sapiens
4.1.1.28 additional information successful strategies to inhibit the decarboxylase have included the synthesis of fluoro-derivatives, which act as competitive and/or suicide inhibitors, as it is the case of several fluoro-dopa derivatives Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
4.1.1.22 endoplasmic reticulum lumen the C-terminus is probably required for sorting the enzyme to the endoplasmic reticulum (ER), after which it can be removed to render the active form of the enzyme located in ER lumen Homo sapiens 5788
-
4.1.1.28 cytosol
-
Homo sapiens 5829
-
4.1.1.28 additional information the enzyme is associated with the membrane in dopamine pro-ducing cells such as neurons, leukocytes and kidney cancer cells Homo sapiens
-
-

Molecular Weight [Da]

EC Number Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
4.1.1.22 additional information
-
processing intermediates of about 63 kDa with potential residual activity are observed in some cell types Homo sapiens
4.1.1.22 53000 55000 active enzyme form Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
4.1.1.22 L-histidine Homo sapiens
-
histamine + CO2
-
?
4.1.1.28 L-Dopa Homo sapiens
-
dopamine + CO2
-
?

Organism

EC Number Organism UniProt Comment Textmining
4.1.1.22 Homo sapiens P19113
-
-
4.1.1.28 Homo sapiens P20711
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
4.1.1.22 proteolytic modification the processing to the active form of mammalian HDC relies on the proteinase activity of caspase 9 and the tandem aspartate residues Asp517-Asp518, Asp550-Asp551 Homo sapiens

Source Tissue

EC Number Source Tissue Comment Organism Textmining
4.1.1.22 brain substancia nigra and hypothalamus Homo sapiens
-
4.1.1.22 colon sigmoid and transverse Homo sapiens
-
4.1.1.22 hypothalamus
-
Homo sapiens
-
4.1.1.22 ileum terminal Homo sapiens
-
4.1.1.22 kidney cortex Homo sapiens
-
4.1.1.22 lung
-
Homo sapiens
-
4.1.1.22 additional information human HDC expression is mainly detected in hypothalamus, lung and stomach in comparison with the rest of the tissues Homo sapiens
-
4.1.1.22 stomach HDC expression regulation in histamine producing gastric cells Homo sapiens
-
4.1.1.28 brain in substantia nigra Homo sapiens
-
4.1.1.28 breast cancer cell different splicing variants Homo sapiens
-
4.1.1.28 colon sigmoid and transverse Homo sapiens
-
4.1.1.28 colonic cancer cell different splicing variants Homo sapiens
-
4.1.1.28 gastric cancer cell different splicing variants Homo sapiens
-
4.1.1.28 ileum terminal Homo sapiens
-
4.1.1.28 kidney cortex Homo sapiens
-
4.1.1.28 kidney cancer cell different splicing variants Homo sapiens
-
4.1.1.28 liver
-
Homo sapiens
-
4.1.1.28 lung DDC is expressed in neuroendocrine differentiated cells Homo sapiens
-
4.1.1.28 additional information neuronal and non-neuronal tissues express DDC mRNAs with distinct 5'-UTR due to alternative promotor usage and alternative splicing within the 5'-UTR. Different splicing variants are observed in cancer cells. The human DDC gene is highly expressed in substantia nigra, terminal ileum,colon transverse, kidney cortex, liver, and pancreas Homo sapiens
-
4.1.1.28 pancreas
-
Homo sapiens
-
4.1.1.28 renal proximal tubule
-
Homo sapiens
-
4.1.1.28 stomach
-
Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
4.1.1.22 L-histidine
-
Homo sapiens histamine + CO2
-
?
4.1.1.28 L-Dopa
-
Homo sapiens dopamine + CO2
-
?

Subunits

EC Number Subunits Comment Organism
4.1.1.22 dimer structure analysis, overview Homo sapiens
4.1.1.22 More the 150 amino acid long C-terminal region present in mammalian HDC but absent in homologous Gram-negative bacteria HDC and all mammalian DDCs. The C-terminus has not got a well-defined secondary structure and it must be removed to reach the active conformation of mammalian HDC. The C-terminus is probably required for sorting the enzyme to the endoplasmic reticulum (ER), after which it can be removed to render the active form of the enzyme located in ER lumen Homo sapiens
4.1.1.28 dimer structure analysis, overview Homo sapiens
4.1.1.28 More a 150 amino acid long C-terminal region is present in mammalian HDC but absent in homologous Gram-negative bacteria HDC and all mammalian DDCs Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
4.1.1.22 HDC
-
Homo sapiens
4.1.1.28 AADC
-
Homo sapiens
4.1.1.28 Aromatic L-amino acid decarboxylase
-
Homo sapiens
4.1.1.28 DDC
-
Homo sapiens
4.1.1.28 dopa decarboxilase
-
Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
4.1.1.22 pyridoxal 5'-phosphate
-
Homo sapiens
4.1.1.28 pyridoxal 5'-phosphate
-
Homo sapiens

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
4.1.1.22 0.0002
-
pH and temperature not specified in the publication Homo sapiens 4(5)-aminooxymethylimidazole

Expression

EC Number Organism Comment Expression
4.1.1.22 Homo sapiens HDC transcription is repressed by Kruppel-like factor 4 (KLF4) interacting at the level of Sp1 binding site, and by the nuclear factors Ying-yang 1 and SREBP-1a that interact with the GC box. The histone acetyl transferases KAT5 (also named as TIP60) and HDAC7 seem to be involved in this mechanisms of KLF4-mediated HDC repression acting as corepressors down
4.1.1.22 Homo sapiens in histamine producing immune cells, HDC expression is modulated by a long list of different stimulus, including lipopolysaccharydes, polypeptides (for instance, neuropeptide P, cytokines), inflammation regulators (for instance, phorbolesters plus dexamethasone), or other compounds (for instance, the intracelular levels of polyamines). Helicobacter pylori infection promotes HDC expression through a signaling pathway involving the trans-elements Rap1 and beta-ra up
4.1.1.28 Homo sapiens in lung, DDC expression in neuroendocrine differentiated cells is upregulated by Notch-1 receptor-elicited signaling up

General Information

EC Number General Information Comment Organism
4.1.1.22 malfunction truncated forms of the enzyme are related to the Gilles de la Tourette syndrome, phenotype MIM number 137580. Single nucleotide polymorphisms are related to nicotine dependence and other additive behaviors. Gene-disease associations and common pathologies, detailed overview Homo sapiens
4.1.1.22 additional information structural and functional analogies and differences between histidine decarboxylase and aromatic L-amino acid decarboxylase (EC 4.1.1.28) molecular networks, overview. Human histidine decarboxylase (HDC) and dopa decarboxylase (DDC) are highly homologous enzymes responsible for the synthesis of biogenic amines (BA) like histamine, and serotonin and dopamine, respectively Homo sapiens
4.1.1.22 physiological function the enzyme is responsible for the biosynthesis of histamine. It is involved in common physiological functions, such as neurotransmission, gastrointestinal track function, immunity, cell growth and cell differentiation. Tissue-specific and time-specific transcriptional HDC regulation must exist, as it behaves as an inducible gene expressed in a very reduced set of cell types. The complexity of HDC expression regulatory mechanisms is also increased by the fact that the enzyme needs to be activated by proteolytic processing and posttranscriptional regulatory mechanisms at the level the enzyme turnover level cannot be discarded. Memory seems to be an important physiological function involving histamine, dopamine, and serotonin Homo sapiens
4.1.1.28 malfunction gene-disease associations and common pathologies, detailed overview Homo sapiens
4.1.1.28 additional information structural and functional analogies and differences between histidine decarboxylase (EC 4.1.1.22) and aromatic L-amino acid decarboxylase molecular networks, overview. Human histidine decarboxylase (HDC) and dopa decarboxylase (DDC) are highly homologous enzymes responsible for the synthesis of biogenic amines (BA) like histamine, and serotonin and dopamine, respectively Homo sapiens
4.1.1.28 physiological function the enzyme is responsible for the biosynthesis of dopamine. It is involved in common physiological functions, such as neurotransmission, gastrointestinal track function, immunity, cell growth and cell differentiation. Memory seems to be an important physiological function involving histamine, dopamine, and serotonin Homo sapiens