In humans, the CD38 protein is encoded by theCD38gene which is located onchromosome 4.[7][8]CD38 is aparalog ofCD157, which is also located on chromosome 4 (4p15) in humans.[9]
CD38 is most frequently found onplasma B cells, followed by natural killer cells, followed by B cells and T cells, and then followed by a variety of cell types.[12]
CD38 can function either as a receptor or as an enzyme.[13] As a receptor, CD38 can attach toCD31 on the surface ofT cells, thereby activating those cells to produce a variety ofcytokines.[13] CD38 activation cooperates with TRPM2 channels to initiate physiological responses such as cell volume regulation.[14]
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 thecytosol performing the same enzymatic functions.[20]
CD38 is believed to control or influenceneurotransmitter release in the brain by producing cADPR.[21] CD38 within the brain enables release of the affiliativeneuropeptideoxytocin.[22]
Like CD38,CD157 is a member of the ADP-ribosyl cyclase family of enzymes thatcatalyze the formation of cADPR from NAD+, although CD157 is a much weaker catalyst than CD38.[23] TheSARM1 enzyme also catalyzes the formation of cADPR from NAD+,[20] but SARM1 elevates cADPR much more efficiently than CD38.[24]
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 toHIV 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 ofasthmatic patients, and amplifies the inflammatory response of airway smooth muscle of those patients.[16]
The use of Daratumumab can interfere with pre-blood transfusion tests, as CD38 is weakly expressed on the surface oferythrocytes. 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 theerythrocytes withdithiothreitol (DTT) or by using an anti-CD38 antibody neutralizing agent, e.g. DaraEx.
A gradual increase in CD38 has been implicated in the decline ofNAD+ with age.[49][50] Treatment of old mice with a specific CD38 inhibitor,78c, prevents age-related NAD+ decline.[51] CD38knockout 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, miceoverexpressing CD38 exhibit reduced NAD+ andmitochondrial 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 invisceral fat and other tissues with age, leading to chronicinflammation.[55] The inflammatorytranscription factorNF-κB and CD38 are mutually activating.[54]Secretions fromsenescent 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.
^Orciani M, Trubiani O, Guarnieri S, Ferrero E, Di Primio R (October 2008). "CD38 is constitutively expressed in the nucleus of human hematopoietic cells".Journal of Cellular Biochemistry.105 (3):905–12.doi:10.1002/jcb.21887.PMID18759251.S2CID44430455.
^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.doi:10.1152/physrev.00035.2007.PMID18626062.
^Deaglio S, Mehta K, Malavasi F (January 2001). "Human CD38: a (r)evolutionary story of enzymes and receptors".Leukemia Research.25 (1):1–12.doi:10.1016/S0145-2126(00)00093-X.PMID11137554.
^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.doi:10.1358/dot.2016.52.10.2543308.PMID27910963.
^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.doi:10.1111/vox.12653.PMID29781081.S2CID29156699.
^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.doi:10.1016/j.bmcl.2011.05.022.PMID21641214.
^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.doi:10.1021/acs.jmedchem.5b00992.PMID26267483.
^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.doi:10.1016/j.bmc.2018.03.021.PMID29576271.
^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.Bibcode:2019SQER...30...21S.doi:10.1080/1062936X.2018.1545695.PMID30489181.S2CID54158219.
^Raab MS, Engelhardt M, Blank A, Goldschmidt H, Agis H, Blau IW, et al. (May 2020). "MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial".The Lancet. Haematology.7 (5):e381 –e394.doi:10.1016/S2352-3026(19)30249-2.PMID32171061.S2CID212718499.
^Lagu B, Wu X, Kulkarni S, Paul R, Becherer JD, Olson L, et al. (July 2022). "Orally Bioavailable Enzymatic Inhibitor of CD38,MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart".Journal of Medicinal Chemistry.65 (13):9418–9446.doi:10.1021/acs.jmedchem.2c00688.PMID35762533.S2CID250090300.
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