Cyclic ADP-ribose
Encyclopedia
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
at the 5' position, which, in turn, closes the cycle by glycosidic bond
ing to the nitrogen 1 (N1) of the same adenine
base (whose position N9 has the glycosidic bond to the other ribose
). 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
(NAD+) by ADP-ribosyl cyclases (EC 3.2.2.5) as part of a second messenger system
.
. It is the physiological allosteric modulator of the ryanodine receptor
(RyR), which stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca2+. RyR activation with high concentration of caffeine
is partly due to caffeine's mimicking the binding of cADPR to RyRs. Whether the action is by direct binding to RyR or indirect (through binding with FKBP12.6) is debated. Some reports suggest that cADPR binding makes FKBP12.6, which normally binds RyR2, to fall off the RYR2.
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, has been reported.
Cyclic ADP-ribose and NAADP. The first book on these two second messengers.
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
) with two phosphate groups present on 5' OH of the adenosine (like ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
), further connected to another ribose
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
at the 5' position, which, in turn, closes the cycle by glycosidic bond
Glycosidic bond
In chemistry, a glycosidic bond is a type of covalent bond that joins a carbohydrate molecule to another group, which may or may not be another carbohydrate....
ing to the nitrogen 1 (N1) of the same adenine
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
base (whose position N9 has the glycosidic bond to the other ribose
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
). 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
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
(NAD+) by ADP-ribosyl cyclases (EC 3.2.2.5) as part of a second messenger system
Second messenger system
Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. They relay the signals of hormones like epinephrine , growth factors, and others, and cause some kind of change in the activity of the cell...
.
Function
cADPR is a cellular messenger for calcium signalingCalcium signaling
Calcium is a common signaling mechanism, as once it enters the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins...
. It is the physiological allosteric modulator of the ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
(RyR), which stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca2+. RyR activation with high concentration of caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
is partly due to caffeine's mimicking the binding of cADPR to RyRs. Whether the action is by direct binding to RyR or indirect (through binding with FKBP12.6) is debated. Some reports suggest that cADPR binding makes FKBP12.6, which normally binds RyR2, to fall off the RYR2.
Metabolism
cADPR and ADPR are synthesized from NAD+ by the bifunctional ectoenzymes of the CD38CD38
CD38 , also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells , including CD4+, CD8+, B and natural killer cells...
family (also includes the GPI-anchored CD157 and the specific, monofunctional ADP ribosyl cyclase of the mollusc Aplysia
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. The general description of sea hares can be found in the article on the superfamily Aplysioidea....
). 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, has been reported.
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.