Enzymes (Isoenzyme System) as homeostatic mechanisms the isoenzyme (ADA2) of adenosine deaminase of human monocytes‐macrophages as a regulator of the 2′deoxyadenosine

Gakis, C; Cappio-Borlino, A.; Pulina, Giuseppe

doi:10.1080/15216549800204012

Cited by 12 publications

(15 citation statements)

References 11 publications

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“…This results in a homeostatic mechanism for the upregulation of 2'deoxyadenosine inside monocytes-macrophages [11].…”

Section: Isoenzyme Ada2 (Ada1-ada2 Isoenzymatic System)mentioning

confidence: 99%

Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role

Gakis¹

1996

Eur Respir J

139

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The isoenzymes ADA1 and ADA2 of the enzyme adenosine deaminase (ADA 3.5.4.4) deaminate mainly two nucleosides: adenosine and 2'deoxyadenosine, producing inosine and 2'deoxyinosine. Adenosine and 2'deoxyadenosine are molecules with many effects on human cells [1][2][3][4]. Thus, the homeostasis of these substances and the activity of the isoenzymes ADA1 and ADA2 in human cells are of extreme importance. Isoenzyme ADA1In humans, the isoenzyme ADA1 is ubiquitous and guarantees the downregulation of the substrates adenosine and 2'deoxyadenosine [1]. This homeostasis is particularly important because a low level of 2'deoxyadenosine is essential for a proper function in immune cells [2][3][4][5]. The isoenzyme ADA1 is also present in red cells, which are equipped with an efficient mechanism to capture and internalize 2'deoxyadenosine. Therefore, in humans, red cells form a "dialysis" system for circulating 2'deoxyadenosine and, in this way, preserve the nucleated cells from an excessive external supply of 2'deoxyadenosine [6].The importance of ADA1 in cells is revealed by the disfunction of the immune response in subjects congenitally lacking ADA1 due to inadequate homeostasis of 2'deoxyadenosine in their immune cells [2,4,6]. There are several other important effects of the substrate adenosine which also bear witness to the importance of the presence of ADA1 in the human body [7]; these will not be discussed here.The Km of ADA1 is 5.2×10 -5 M. ADA1 has an optimal pH of 7-7.5 and a similar affinity for both adenosine and 2'deoxyadenosine (2'deoxyadenosine/adenosine deaminase ratio of 0.75) [1,8].These features make ADA1 highly efficient in deaminating the substrates (adenosine and 2'deoxyadenosine) in biological sites where the pH is optimal for this isoenzyme even though the substrate concentration is very low. Isoenzyme ADA2 (ADA1-ADA2 isoenzymatic system)The isoenzyme ADA2 is not ubiquitous, but coexists with ADA1 only in monocytes-macrophages. ADA2 and ADA1 are coded by different gene loci [1,4,9,10].The Km of ADA2 is 200×l0 -5 M; ADA2 has an optimum pH of 6.5 and a weak affinity for 2'deoxyadenosine (2'deoxyadenosine/adenosine deaminase ratio of 0.25) [1,8,9]. These features make ADA2 inefficient in deaminating 2'deoxyadenosine in biological sites where the pH is higher than the optimum for this isoenzyme and the concentration of substrates is too low.Why, therefore, should ADA2 be present in monocytesmacrophages, where conditions are not suitable for its optimum function? To answer this question, which is extremely important from a biological point of view, it is necessary to consider ADA1 and ADA2 as a system which acts to guarantee the homeostasis of adenosine and 2'deoxyadenosine in monocytes-macrophages. This homeostatic mechanism involves two substrates and two isoenzymes. Both isoenzymes have similar affinity for the substrate adenosine, whilst ADA2 has a different affinity (very weak) for the substrate 2'deoxyadenosine [1,8].Through the simulation model STELLA II (High Performance System Inc., 1993), we h...

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“…This results in a homeostatic mechanism for the upregulation of 2'deoxyadenosine inside monocytes-macrophages [11].…”

Section: Isoenzyme Ada2 (Ada1-ada2 Isoenzymatic System)mentioning

confidence: 99%

Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role

Gakis¹

1996

Eur Respir J

139

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“…ADA2 found only in monocytes and macrophages is released extracellularly during infections or chronic inflammation as observed in type 2 DM [23]. ADA2-dependent T cell proliferation and monocyte-macrophage differentiation /proliferation may explain predominantly increased serum ADA2 activity compared to ADA1 in this study.…”

Section: Discussionmentioning

confidence: 47%

Diagnostic Value of Adenosine Deaminase and its Isoenzymatic Activity in Nepalese Patients with Type 2 Diabetes Mellitus

Sapkota¹,

Pokharel²,

Shukla³

et al. 2017

CMRA

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“…ADA2 is thought to regulate the concentration of 2′-deoxyadenosine, which is part of an innate response against offending intracellular microorganisms15. Few in-vitro studies have detected elevated ADA production in THP-1 and MDM cells infected with live MTB89.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisESAT6 and CPF10 Induce Adenosine Deaminase 2 mRNA Expression in Monocyte-Derived Macrophages

et al. 2017

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BackgroundDelayed hypersensitivity plays a large role in the pathogenesis of tuberculous pleural effusion (TPE). Macrophages infected with live Mycobacterium tuberculosis (MTB) increase the levels of adenosine deaminase2 (ADA2) in the pleural fluid of TPE patients. However, it is as yet unclear whether ADA2 can be produced by macrophages when challenged with MTB antigens alone. This study therefore evaluated the levels of ADA2 mRNA expression, using monocyte-derived macrophages (MDMs) stimulated with MTB antigens.MethodsPurified monocytes from the peripheral blood mononuclear cells of healthy volunteers were differentiated into macrophages using granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF). The MDMs were stimulated with early secretory antigenic target protein 6 (ESAT6) and culture filtrate protein 10 (CFP10). The mRNA expression levels for the cat eye syndrome chromosome region, candidate 1 (CECR1) gene encoding ADA2 were then measured.ResultsCECR1 mRNA expression levels were significantly higher in MDMs stimulated with ESAT6 and CFP10, than in the unstimulated MDMs. When stimulated with ESAT6, M-CSF-treated MDMs showed more pronounced CECR1 mRNA expression than GM-CSF-treated MDMs. Interferon-γ decreased the ESAT6- and CFP10-induced CECR1 mRNA expression in MDMs. CECR1 mRNA expression levels were positively correlated with mRNA expression of tumor necrosis factor α and interleukin 10, respectively.ConclusionADA2 mRNA expression increased when MDMs were stimulated with MTB antigens alone. This partly indicates that pleural fluid ADA levels could increase in patients with culture-negative TPE. Our results may be helpful in improving the understanding of TPE pathogenesis.

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Enzymes (Isoenzyme System) as homeostatic mechanisms the isoenzyme (ADA2) of adenosine deaminase of human monocytes‐macrophages as a regulator of the 2′deoxyadenosine

Cited by 12 publications

References 11 publications

Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role

Adenosine deaminase (ADA) isoenzymes ADA1 and ADA2: diagnostic and biological role

Diagnostic Value of Adenosine Deaminase and its Isoenzymatic Activity in Nepalese Patients with Type 2 Diabetes Mellitus

Mycobacterium tuberculosisESAT6 and CPF10 Induce Adenosine Deaminase 2 mRNA Expression in Monocyte-Derived Macrophages

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