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 (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 compo ...

at the 5' position, which, in turn, closes the cycle by

glycosidic bond A glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate. A glycosidic bond is formed between the hemiacetal or hemiketal group ...

ing to the nitrogen 1 (N¹) of the same

adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deri ...

base (whose position N⁹ has the glycosidic bond to the other

). The N¹-glycosidic bond to adenine is what distinguishes cADPR from

ADP-ribose Adenosine diphosphate ribose (ADPR) is an ester molecule formed into chains by the enzyme poly ADP ribose polymerase. ADPR is created from cyclic ADP-ribose (cADPR) by the CD38 enzyme using nicotinamide adenine dinucleotide (NAD+) as a cofactor. ...

(ADPR), the non-cyclic analog. cADPR is produced from nicotinamide adenine dinucleotide (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 or cell signaling, encompassing both first me ...

Function

cADPR is a cellular messenger for

calcium signaling Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allos ...

. It stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca²⁺. The primary target of cADPR is the endoplasmic reticulum 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 for the TRPM2 channel, but less potently than ADPR. cADPR and ADPR act

synergistically Synergy is an interaction or cooperation giving rise to a whole that is greater than the simple sum of its parts. The term ''synergy'' comes from the Attic Greek word συνεργία ' from ', , meaning "working together". History In Christia ...

, 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 The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are ke ...

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 ''Aplysia'' () is a genus of medium-sized to extremely large sea slugs, specifically sea hares, which are one clade of large sea slugs, marine gastropod mollusks. These benthic herbivorous creatures can become rather large compared with most ...

''). 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 Sterile alpha and TIR motif containing 1 Is an enzyme that in humans is encoded by the ''SARM1'' gene. It is the most evolutionarily conserved member of the Toll/Interleukin receptor-1 (TIR) family. SARM1's TIR domain has intrinsic NADase enzym ...

and other

TIR domain Members of the very wide interleukin-1 receptor (IL-1R) family are characterized by extracellular immunoglobulin-like domains and intracellular Toll/Interleukin-1R (TIR) domain. It is a group of structurally homologous proteins, conserved througho ...

-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

-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

-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