Cyclic ADP Ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
) 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 building ...
(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 (N
1) 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 derivati ...
base (whose position N
9 has the glycosidic bond to the other
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 ...
). The N
1-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
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
(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 all ...
. It stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca
2+. The primary target of cADPR is the
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
Ca
2+ uptake mechanism. cADPR mobilizes Ca
2+ from the endoplasmic reticulum by activation of
ryanodine receptor
Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons.
There are three major isoforms of the ryanodine receptor, which are found in different tissu ...
s,
a critical step in muscle contraction.
cADPR also acts as an
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
for the
TRPM2
Transient receptor potential cation channel, subfamily M, member 2, also known as TRPM2, is a protein that in humans is encoded by the ''TRPM2'' gene.
Structure
The protein encoded by this gene is a non-selective calcium-permeable cation channel ...
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 Christi ...
, with both molecules enhancing the action of the other molecule in activating the TRPM2 channel.
Potentiation of Ca
2+ release by cADPR is mediated by increased accumulation of Ca
2+ 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 Cell (biology), cells. The main function of the SR is to store calcium ions (Ca2+). Calcium in bio ...
.
Metabolism
cADPR and ADPR are synthesized from NAD
+ by the bifunctional ectoenzymes of the
CD38
CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in ...
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 N
1-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
High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
retention times compared to canonical cADPR have been identified as products of bacterial and plant
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 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
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 can act as an activator of bacterial antiphage defense systems and as a suppressor of plant immunity.
See also
*
NAADP
Nicotinic acid adenine dinucleotide phosphate, (NAADP), is a Ca2+-mobilizing second messenger synthesised in response to extracellular stimuli. Like its mechanistic cousins, IP3 and cyclic adenosine diphosphoribose (Cyclic ADP-ribose), NAADP bind ...
*
IP3
*
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.
...
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