AOC1 Gene and Histamine Regulation

Introduction

Amiloride sensitive amine oxidase (P19801) Protein is produced in Homo sapiens (human) by the expression of the gene AOC1. It Catalyzes the degradation of compounds such as putrescine, histamine, spermine, and spermidine, substances involved in allergic and immune responses, cell proliferation, tissue differentiation, tumor formation, and possibly apoptosis It is observed that the highest levels of DAO expression occurs in the digestive tract and the placenta (Kirschner et al, 2014). In humans, a certain subtype of cells of the placenta, namely the extravillous trophoblast, express the enzyme and secrete it into the blood stream of a pregnant woman. Lowered diamine oxidase values in maternal blood in early pregnancy might be an indication for trophoblast-related pregnancy disorders like early-onset preeclampsia. Normally the enzyme is not or only very scarce present in the blood circulation of humans, but it increases vastly in pregnant women suggesting a protective mechanism against adverse histamine. It is also secreted by eosinophil. In case of a shortage of diamine oxidase in the human body, it may appear as an allergy or histamine intolerance. Placental DAO is thought to play a role in the regulation of the female reproductive function.

Reactions

This protein acts as an enzyme. It is known to catalyze the following reaction

Putrescine + Oxygen + Water → 4-Aminobutyraldehyde + Ammonia + Hydrogen peroxide

Histamine+Water+Oxygen=Imidazole-4-acetaldehyde+Ammonia+Hydrogen peroxide

Inhibitors

It is inhibited by isonoazid, cimetidin, Clonidine, pentamidine, berenil, pentaamidine

CO FACTORS

It requires the following co factors: Cu cation CHEBI: 23378

Ca (2+) CHEBI: 2910

L-topaquinone CHEBI: 79027

Analysis of the DNA Sequence of P19801-2 Protein:

The analysis of the organization of the sequence of the human ABP/DAO gene has been done by Lingueglia, E., Renard, S., Voilley, N., Waldmann, R., Chassande, O., Lazdunski, M., and Barbry, P. (1993) The gene analysis reveals that the 2.4-kilobase messenger RNA is transcribed from two close origins identifying the proximal promoter. After sequencing, some corrections within the initial cDNA sequence have been made. Human ABP/DAO corresponds to a 751-residue polypeptide. The promoter activity of 1800 base pairs upstream of the transcription start sites of the long form has been analyzed. Two bulks of cis-activating sequences have been identified. One of them constitutes the proximal promoter. It contains a palindromic sequence previously described as E-PAL. This motif is essential for the full activity of the promoter and behaves like a composite element. The first molecular cloning of a human gene coding for a diamine oxidase will allow us to further understand its regulation during cell growth and/or embryonic development.

P19801-2 Sequence variations

Genes for two forms of human placenta diamine oxidase (dao) were cloned from a cDNA library and sequenced by Zhang X, Kim J, McIntire WS (1995). One gene, pdao1, is identical in length to human kidney dao but differs from it by two bases in the coding region and differs slightly in the 3'- and 5'-noncoding regions. The second gene, pdao2, is nearly identical to these genes in the coding region, except that it has an extra 57-nucleotide coding segment near the 3' end of this region. This segment corresponds to the contiguous sequence of the 3' end of intron 3 of human kidney dao.pdao2 also differs significantly from pdao1 and human kidney dao in a 13-base sequence in the 5'-noncoding region. It is proposed that pdao1 and human kidney dao are polymorphic forms of the same allele. Whether pdao2 is a polymorph of these two is not certain, because of the significant differences in the coding and noncoding regions. Pdao2 may represent a different allele Phenamil, an analog of amiloride, is a potent blocker of the epithelial Na+ channel. It has been used by Barby P, Champe M, Chassande O, et. al (1990) to purify the porcine kidney amiloride-binding protein. Synthetic oligonucleotides derived from partial sequences have been used to screen a human kidney cDNA library and to isolate the cDNA encoding the human amiloride-binding protein. The primary structure was deduced from the DNA sequence analysis. The protein is 713 residues long, with a 19-amino acid signal peptide. The mRNA was expressed in 293-S and NIH 3T3 cells, yielding a glycoprotein (i) that binds amiloride and amiloride analogs with affinities similar to the amiloride receptor associated with the apical Na+ channel in pig kidney membranes and (ii) that is immunoprecipitated with monoclonal antibodies raised against pig kidney amiloride-binding protein. Diamine oxidase (histaminase), an enzyme that oxidatively deaminates putrescine and histamine, was purified from human placenta and from pig kidney by Novotny W , Chassande O, Baker M, Lazdunski M, Barbry P(1994). Both NH2-terminal sequences are highly homologous to the human kidney amiloride-binding protein, previously thought to be a component of the amiloride-sensitive Na+ channel. Monoclonal antibodies raised against the pig kidney amiloride-binding protein immunoprecipitate a polypeptide with the same M(r) (105,000) as that of pig kidney diamine oxidase. That polypeptide has both diamine oxidase activity and the capacity to bind [3H] phenamil, a tritiated amiloride derivative. Cells stably transfected with human kidney amiloride-binding protein cDNA express a high diamine oxidase activity. In transfected cells as well as with the purified enzyme, this activity was inhibited by amiloride and by some of its derivatives, such as phenamil and ethylpropylamiloride. Amiloride inhibition seems to be due to drug binding at the active site of the enzyme. These data indicate that human placental diamine oxidase is identical to the human kidney amiloride-binding protein and that amiloride analogues may have wider physiological effects besides those on epithelial ion transport.

Related research studied on DAO

Diamine oxidase (DAO) oxidatively deaminates histamine and other diamines. Due to the lack of antibodies for human DAO, many findings on this enzyme had not been confirmed in man. Therefore, a series of monoclonal antibodies is produced by Hubert G Schwelberger, Johannes Feurle, Gunnar Houen (2013) by immunizing mice with human DAO protein fragments expressed in vitro. Five different monoclonal antibodies specific for human DAO were obtained that do not recognize any other human protein and can detect DAO with 100-fold greater sensitivity than the most sensitive enzymatic assays currently available. Using these antibodies allowed confirming the expression and cellular localization of DAO in various human tissues such as kidney, intestine and placenta where the presence of the enzyme had previously been deduced from activity measurement and DAO mRNA analysis. Due to the high sensitivity of the novel monoclonal antibodies, DAO was also detected at sites that previously evaded unequivocal proof of DAO enzymatic activity such as the urine. On the other hand, with these antibodies it was possible to show that DAO is normally not present in human liver and blood serum. The new monoclonal antibodies not only allow a comprehensive quantitative evaluation of the expression of DAO at the cellular level in man but will also facilitate sensitive analyses of disease-associated alterations of this enzyme. Diamine oxidase (DAO) is essential for extracellular degradation of histamine. For decades activity assays with inherent limitations were used to quantify the relative amounts of DAO. No reference DAO standard is available. Absolute DAO amounts cannot be determined. Controversy exists, whether DAO is circulating or not in non-pregnant individuals. The role of DAO as biomarker in various diseases is ambiguous. It is not clear, whether precise quantification of human DAO antigen using commercially available enzyme-linked immunosorbent assays (ELISAs) is possible. The objective was to develop a precise and robust ELISA to quantify DAO in various biological fluids. The study was conducted by Gludovacz, Maresch et al (2017). Histamine intolerance is a disorder in the homeostasis of histamine due to a reduced intestinal degradation of this amine, mainly caused by a deficiency in the enzyme diamine oxidase (DAO). Among the several multi-faced symptoms associated with histamine intolerance, headache is one of the most recognized and disabling consequences. Izquierdo-Casas , Comas-Basté , Latorre-Moratalla (2018) conducted their study in a bid to determine the prevalence of DAO deficiency in patients with a confirmed migraine diagnosis according to the current International Headache Society (IHS) and in non-migraine subjects. DAO activity was assessed in a total of 198 volunteers recruited at the Headache Unit of the Hospital General de Catalunya, 137 in the migraine group and 61 as a control group. DAO enzyme activity in blood samples was determined by ELISA test. Values below 80 HDU/ml (Histamine Degrading Unit/ml) were considered as DAO deficient. Mean value of DAO activity from migraine population (64.5 ± 33.5 HDU/ml) was significantly lower (p < 0.0001) than that obtained from healthy volunteers (91.9 ± 44.3 HDU/ml). DAO deficiency was more prevalent in migraine patients than in the control group. A high incidence rate of DAO deficiency (87%) was observed in the group of patients with migraine. On the other hand, 44% of non-migranous subjects had levels of DAO activity lower than 80 HDU/ml. Despite the multifactorial aetiology of migraine, these results seem to indicate that this enzymatic deficit could be related to the onset of migraine.

The amine oxidase DAO, formerly called histaminase, is found in various tissues, but is especially active in the intestinal mucosa. Its function is the oxidative deaminating of several polyamines, essential substances for cell proliferation. DAO is thus a regulating enzyme in rapidly proliferating tissues such a bone marrow and intestinal mucosa. Results from several studies have demonstrated that both ornithine decarboxylase (ODC) and DAO activity rise during adaptive hyperplasia seen after small bowel resection. The ODC-dependent increase in polyamine content and subsequent increase in cell proliferative activity is probably down regulated locally in the villus tip by the increased DAO activity. DAO is normally present in very small amounts in the circulation and its basal plasma levels are positively correlated with the maturity and integrity of the intestinal mucosa. After intravenous administration of heparin, DAO is released from its capillary binding sites in the lamina propria into the peripheral circulation. Measurement of postheparin DAO release enhances its sensitivity and is now extensively studied to assess its value as follow-up or screening test for several enteropathies. Measuring basal as well as postheparin DAO levels has potential relevance following small bowel transplantation. Rejection of the small bowel graft leads to mucosal damage, which could conceivably lead to changes in DAO activity

REFERENCES

Barbry P, Champe M, Chassande O, Munemitsu S, Champigny G, Lingueglia E, Maes P, Frelin C,Tartar A, Ullrich A. (1990) Human kidney amiloride-binding protein: cDNA structure and functional expression. Proc Natl Acad Sci U S A;87(19):7347-51.

Chassande O, Renard S, Barbry P, Lazdunski M. (1994) The human gene for diamine oxidase, an amiloride binding protein. Molecular cloning, sequencing, and characterization of the promoter. J Biol Chem; 269(20):14484-9

Gludovacz E, Maresch D, Lopes de Carvalho L, Puxbaum V, Baier L, Sutzl L, Guedez G, Grunwald- Gruber C, Ulm B, Pils S, Ristl R, Altmann F, Jilma B, Salminen T, Borth N, Boehm T. (2017) Oligomannosidic glycans at Asn110 are essential for seretion of human diamine oxidase. JBC. M117.814244

Hubert G, Feurle J, Houen G. (2013) New Tools for Studying Old Questions: Antibodies for Human Diamine Oxidase. J Neural Transm.Vienna; 120 (6), 1019

Izquierdo-Casas’ J, Comas-Basté O, Luz Latorre-Moratalla M, Lorente-Gascón M, Duelo A , Vidal-Carou C , Soler-Singla L. (2018) Low Serum Diamine Oxidase (DAO) Activity Levels in Patients With Migraine. J Physiol Biochem, 74 (1), 93-998.

Kirschner K, Braun JF, Jacobi CL, Rudigier LJ, Persson AB., Scholz H. (2014) Amine Oxidase Copper- containing 1 (AOC1) is a Downstream Target Gene of the Wilms Tumor Protein, WT1, during Kidney Development. The Journal of Biological Chemistry

Novotny WF, Chassande O, Baker M, Lazdunski M, Barbry P. (1994) Diamine Oxidase Is the Amiloride-Binding Protein and Is Inhibited by Amiloride Analogues. J Biol Chem 269 (13), 9921-5

Wolvekamp MC, de Bruin RW. (1994) Diamine Oxidase: An Overview of Historical, Biochemical and Functional Aspects. 2 (1), 2-14

Zhang X, Kim J, McIntire WS. (1995) cDNA sequences of variant forms of human placenta diamine oxidase. Biochem Genet. (7-8):261-8.