Cyclic ADP-ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like cAMP) with two phosphate groups present on 5' OH of the

adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...

(like ADP), further connected to another

ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally occurring form, , is a component of the ribonucleotides from which RNA is built, and so this comp ...

at the 5' position, which, in turn, closes the cycle by glycosidic bonding to the nitrogen 1 (N¹) of the same adenine base (whose position N⁹ has the glycosidic bond to the other

). The N¹-glycosidic bond to adenine is what distinguishes cADPR from ADP-ribose (ADPR), the non-cyclic analog. cADPR is produced from

nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphat ...

(NAD⁺) by ADP-ribosyl cyclases ( EC 3.2.2.5) as part of a

second messenger system Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first me ...

Function

cADPR is a cellular messenger for calcium signaling. It stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca²⁺. The primary target of cADPR is the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

Ca²⁺ uptake mechanism. cADPR mobilizes Ca²⁺ from the endoplasmic reticulum by activation of ryanodine receptors, a critical step in muscle contraction. cADPR also acts as an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

for the TRPM2 channel, but less potently than ADPR. cADPR and ADPR act synergistically, with both molecules enhancing the action of the other molecule in activating the TRPM2 channel. Potentiation of Ca²⁺ release by cADPR is mediated by increased accumulation of Ca²⁺ in the sarcoplasmic reticulum.

Metabolism

cADPR and ADPR are synthesized from NAD⁺ by the bifunctional ectoenzymes of the CD38 family (also includes the GPI-anchored CD157 and the specific, monofunctional ADP ribosyl cyclase of the mollusc '' Aplysia''). The same enzymes are also capable of hydrolyzing cADPR to ADPR. Catalysis proceeds via a covalently bound intermediate. The hydrolysis reaction is inhibited by ATP, and cADPR may accumulate. Synthesis and degradation of cADPR by enzymes of the CD38 family involve, respectively, the formation and the hydrolysis of the N¹-glycosidic bond. In 2009, the first enzyme able to hydrolyze the phosphoanhydride linkage of cADPR, i.e. the one between the two phosphate groups, was reported. SARM1 and other TIR domain-containing proteins also catalyze the formation of cADPR from NAD⁺.

Isomers

Variants of cADPR that differ in their HPLC retention times compared to canonical cADPR have been identified as products of bacterial and plant TIR domain-containing enzymes. v-cADPR (also referred to as 2'cADPR or 1''-2' glycocyclic ADPR (gcADPR)) and v2-cADPR (also referred to as 3'cADPR or 1''-3' gcADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. 3'cADPR produced by bacterial TIR domain-containing proteins can act as an activator of bacterial antiphage defense systems and as a suppressor of plant immunity.

References

External links

The web page of Dr. Hon Cheung Lee, the discoverer of cyclic ADP-ribose.
*
Cyclic ADP-ribose and NAADP. The first book on these two second messengers.
{{Nucleobases, nucleosides, and nucleotides Nucleotides Cyclic nucleotides

Function

Metabolism

Isomers

See also

References

External links