CD38 (CD38 molecule; HGNC:1667, NCBI Gene ID 952) is a human locus mapped to chromosome band 4p15.32 that encodes type II transmembrane glycoprotein CD38 NADase / ADP-ribosyl cyclase (300 aa; EC 3.2.2.6). CD38 acts in hydrolysis of NAD+ & NMN to ADP-ribose/cADPR (Ca2+ mobilization) & senescence-driven NAD+ decline, together with NAMPT (NAD+ Salvage Enzyme Gene), SIRT1 (Nuclear Sirtuin 1 Gene), and SIRT3 (Mitochondrial Sirtuin 3 Gene). Encodes the principal mammalian NAD+-degrading glycohydrolase and plasma-cell surface marker targeted by daratumumab.
Approved Symbol
CD38
Chromosomal Locus
4p15.32
Encoded Product
Type II transmembrane glycoprotein CD38 NADase / ADP-ribosyl cyclase (300 aa; EC 3.2.2.6)
Primary Pathway
Hydrolysis of NAD+ & NMN to ADP-ribose/cADPR (Ca2+ mobilization) & senescence-driven NAD+ decline
Clinical / Therapeutic Role
Target of FDA-approved daratumumab & isatuximab in multiple myeloma; small-molecule CD38 inhibitors (78c) restore aged tissue NAD+
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 8-exon gene on chromosome 4p15.32 whose promoter contains NF-kappaB, STAT, and interferon-stimulated response elements strongly induced by the senescence-associated secretory phenotype (SASP), encoding a 45 kDa single-pass type II membrane glycoprotein with a disulfide-stabilized catalytic ectodomain (able to adopt both ecto- and cytosolic-facing type III orientations).
Cellular & Tissue Expression Profile: Expressed at very high density on normal and malignant plasma cells (multiple myeloma), activated T and B lymphocytes, natural killer cells, and pro-inflammatory M1 macrophages that accumulate inside aging white adipose tissue, liver, and skeletal muscle.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Acts as a high-flux NAD+ glycohydrolase and extracellular NMN nucleosidase—consuming ~100 molecules of NAD+ to generate 98–99 molecules of linear ADP-ribose and 1–2 molecules of the second messenger cyclic ADP-ribose (cADPR, plus NAADP at acidic pH), which gate ryanodine receptors and TPC2 channels to mobilize intracellular Ca2+.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: As senescent cells accumulate during chronological aging, SASP cytokines (TNF, IL-6) induce a dramatic expansion of CD38-high tissue-resident macrophages; genetic knockout or catalytic inactivation of CD38 in aged animals completely prevents age-related NAD+ decline, preserves mitochondrial SIRT3 activity, and protects against diet-induced obesity.
Therapeutic & Clinical Pharmacology: Clinically targeted in oncology by FDA-approved anti-CD38 monoclonal antibodies daratumumab (Darzalex) and isatuximab (Sarclisa) for multiple myeloma and AL amyloidosis, and in longevity pharmacology by potent thiazoloquin(az)olinone CD38 catalytic inhibitors (such as 78c) that restore aged tissue NAD+ and physical function.