In humans, the CD38 protein is encoded by the CD38gene which is located on
chromosome 4.[7][8]CD38 is a
paralog of CD157, which is also located on chromosome 4 (4p15) in humans.[9]
CD38 is most frequently found on
plasma B cells, followed by natural killer cells, followed by B cells and T cells, and then followed by a variety of cell types.[12]
Function
CD38 can function either as a receptor or as an enzyme.[13] As a receptor, CD38 can attach to
CD31 on the surface of
T cells, thereby activating those cells to produce a variety of
cytokines.[13] CD38 activation cooperates with TRPM2 channels to initiate physiological responses such as cell volume regulation.[14]
CD38 is a multifunctional
enzyme that catalyzes the synthesis of
ADP ribose (ADPR) (97%) and
cyclic ADP-ribose (cADPR) (3%) from
NAD+.[15][16] CD38 is thought to be a major regulator of NAD+ levels, its NADase activity is much higher than its function as an ADP-rybosyl-cyclase: for every 100 molecules of NAD+ converted to ADP ribose it generates one molecule of cADPR.[17][15] When
nicotinic acid is present under acidic conditions, CD38 can hydrolyze
nicotinamide adenine dinucleotide phosphate (NADP+) to
NAADP.[15][18]
These reaction products are essential for the regulation of intracellular Ca2+.[19] CD38 occurs not only as an ectoenzyme on cell outer surfaces, but also occurs on the inner surface of cell membranes, facing the
cytosol performing the same enzymatic functions.[20]
CD38 is believed to control or influence
neurotransmitter release in the brain by producing cADPR.[21] CD38 within the brain enables release of the affiliative
neuropeptideoxytocin.[22]
Like CD38,
CD157 is a member of the ADP-ribosyl cyclase family of enzymes that
catalyze the formation of cADPR from NAD+, although CD157 is a much weaker catalyst than CD38.[23] The
SARM1 enzyme also catalyzes the formation of cADPR from NAD+,[20] but SARM1 elevates cADPR much more efficiently than CD38.[24]
Clinical significance
The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.[19][25]
The CD38 protein is a marker of cell activation. It has been connected to
HIV infection,
leukemias,
myelomas,[29] solid tumors,
type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.
CD38 increases airway contractility hyperresponsiveness, is increased in the lungs of
asthmatic patients, and amplifies the inflammatory response of airway smooth muscle of those patients.[16]
Clinical application
CD38 inhibitors may be used as therapeutics for the treatment of asthma.[30]
CD38 has been used as a prognostic marker in
leukemia.[31]
The use of Daratumumab can interfere with pre-
blood transfusion tests, as CD38 is weakly expressed on the surface of
erythrocytes. Thus, a screening assay for irregular antibodies against red blood cell antigens or a direct immunoglobulin test can produce false-positive results.[34] This can be sidelined by either pretreatment of the
erythrocytes with
dithiothreitol (DTT) or by using an anti-CD38 antibody neutralizing agent, e.g. DaraEx.
A gradual increase in CD38 has been implicated in the decline of
NAD+ with age.[49][50] Treatment of old mice with a specific CD38 inhibitor,
78c, prevents age-related NAD+ decline.[51] CD38
knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline,[52] with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart).[53] On the other hand, mice
overexpressing CD38 exhibit reduced NAD+ and
mitochondrial dysfunction.[52]
Macrophages are believed to be primarily responsible for the age-related increase in CD38 expression and NAD+ decline.[54]Cellular senescence of macrophages increases CD38 expression.[54] Macrophages accumulate in
visceral fat and other tissues with age, leading to chronic
inflammation.[55] The inflammatory
transcription factorNF-κB and CD38 are mutually activating.[54]Secretions from
senescent cells induce high levels of expression of CD38 on macrophages, which becomes the major cause of NAD+ depletion with age.[56]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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abcMalavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. (July 2008). "Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology". Physiological Reviews. 88 (3): 841–86.
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^Deaglio S, Mehta K, Malavasi F (January 2001). "Human CD38: a (r)evolutionary story of enzymes and receptors". Leukemia Research. 25 (1): 1–12.
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^Xia C, Ribeiro M, Scott S, Lonial S (October 2016). "Daratumumab: monoclonal antibody therapy to treat multiple myeloma". Drugs of Today. 52 (10): 551–560.
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^de Vooght KM, Lozano M, Bueno JL, Alarcon A, Romera I, Suzuki K, et al. (May 2018). "Vox Sanguinis International Forum on typing and matching strategies in patients on anti-CD38 monoclonal therapy: summary". Vox Sanguinis. 113 (5): 492–498.
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^Kellenberger E, Kuhn I, Schuber F, Muller-Steffner H (July 2011). "Flavonoids as inhibitors of human CD38". Bioorganic & Medicinal Chemistry Letters. 21 (13): 3939–42.
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^Becherer JD, Boros EE, Carpenter TY, Cowan DJ, Deaton DN, Haffner CD, et al. (September 2015). "Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38". Journal of Medicinal Chemistry. 58 (17): 7021–56.
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^Deaton DN, Haffner CD, Henke BR, Jeune MR, Shearer BG, Stewart EL, et al. (May 2018). "2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships". Bioorganic & Medicinal Chemistry. 26 (8): 2107–2150.
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^Sepehri B, Ghavami R (January 2019). "Design of new CD38 inhibitors based on CoMFA modelling and molecular docking analysis of 4‑amino-8-quinoline carboxamides and 2,4-diamino-8-quinazoline carboxamides". SAR and QSAR in Environmental Research. 30 (1): 21–38.
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Overview of all the structural information available in the
PDB for
UniProt: P28907 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1) at the
PDBe-KB.