ADP-ribosyl cyclases

Enzymes involved in the metabolism of cADPR have been reported in many tissues. A scheme for the synthesis and a degradation of cADPR is depicted in Fig. 2. 

---

Wilson HL, Dipp M, Thomas JM, Lad C, Galione A, Evans AM 2001 ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor. A primary role for cyclic ADP-ribose in hypoxic pulmonary vasoconstriction. J Biol Chem 276 11180-11188... 

In some cell types (including cardiac muscle cells, pancreatic cells), another second messenger", the cyclic ADP-ribose (Fig. 6.8), is involved in opening the ryanodin receptors (Lee et al., 1994). The cADP-ribose is formed from NAD by an enzymatic pathway with the help of an ADP-ribosyl cyclase. 

Additionally, possible roles for cADPr in regulation of a surface RyR were suggested by demonstrations of cytosolic mRNA for the multifunctional ADP-ribosyl cyclase, CD38 which catalyzes NAD+ cyclization to cADPr, known in turn to gate Ca2+ release through microsomal membrane-resident ryanodine receptors (RyRs). Both confocal microscopy and Western blotting then localized the CD38 protein to the plasma membrane (Sun et al., 1999). 

Adebanjo OA, Anandathreethavarada HK, Koval AP, Moonga BS, Biswas G, Sun L, Sodam BR, Bevis PJR, Huang CL-H, Epstein S, Lai FA, Avadhani NG, Zaidi M. 1999. A new function for CD38/ADP-ribosyl cyclase in nuclear Ca2+ homeostasis. Nature Cell Biology 7 409-414. 

Sun L, Adebanjo OA, Koval A, Anandatheerthavarada HK, Iqbal J, Wu XY, Moonga BS, Wu XB, Biswas G, Bevis PJ, Kumegawa M, Epstein S, Huang CL, Avadhani NG, Abe E, Zaidi M. 2002. A novel mechanism for coupling cellular intermediary metabolism to cytosolic Ca2+ signaling via CD38/ADP-ribosyl cyclase, a putative intracellular NAD+ sensor. FASEB J. 16 302-14. 

Sun L, Adebanjo OA, Moonga BS, Corisdeo S, Anandatheerthavarada HK, Biswas G, Arakawa T, Hakeda Y, Koval A, Sodam B, Bevis PJ, Moser AJ, Lai FA, Epstein S, Troen BR, Kumegawa M, Zaidi M. 1999. CD38/ADP-ribosyl cyclase a new role in the regulation of osteoclastic bone resorption. J Cell Biology 146 1161-71. 

ADP ribosyl cyclase Decreased transmitter release Initiation of hippocampal LTD Hippocampus Fossier et al. 1999 Reyes-Harde et al. 1999a,b... 

Galione A (1994) Cyclic ADP-ribose, the ADP-ribosyl cyclase pathway and calcium signalling. Mol Cell Endocrinol 98 125-31... 

AU-trans-retinoic acid (Section 2.2.S.2) stimulates the synthesis of cADP-ribose in kidney cells in culture, apparendy as a result of the induction of CD38 (Beers et al., 1995 Takahashi et al., 1995) in ovariectomized rats, estradiol induces cytosolic ADP-ribosyl cyclase in the uterus, but not in estrogen unresponsive tissues (Chini et al., 1997). If this induction of ADP-ribose cyclase by estrogens leads to significant depletion of nicotinamide nucleotides, it may provide an additional explanation for the 2 1 excess of females to males in the incidence of pellagra (Section 8.5). 

Chini EN, de Toledo EG, Thompson MA, and Dousa TP (1997) Effect of estrogen upon cyclic ADP ribose metabolism beta-estradiol stimulates ADP ribosyl cyclase in rat uterus. Proceedings of the National Academy of ScierKes of the USA 94, 5872-6. 

NAD serves as a donor of an ADP-ribose group for the synthesis of cyclic ADP-ribose. ADP-ribosyl cyclase catalyzes the synthesis of cyclic ADP-ribose (Figure 9,651 J). This molecule works within the cell and provokes the release of calcium ions from an internal storage site (Jacobson cf al., 1997). The overall concentration of cyclic ADP-ribose in various organs is about 2.0micromolar (Dousa etai, 1996. The action of cyclic ADP-ribose In the cell is thought to be similar to that of another signaling molecule, 1P3 (see Calcium section). 

A carbocyclic NAD(+) analogue (91) incorporating a methylenebisphospho-nate linkage in place of the natural pyrophosphate has been prepared as an inhibitor of ADP-ribosyl cyclase which is resistant to non-specific phosphatase degradation.The analogue 91 was obtained in 25% yield following a Poulter coupling of the precursor 92 with adenosine 5 -methylenebisphosphonate. 

Fig. 6.9 Reactions of ADP ribosyl cyclase. Structures of NADP, nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose phosphate (cADPRP). ADP-ribosyl cyclase, in base ex-...

FI G U R E 2 Metabolism of cyclic ADP-ribose. cADPR is synthesized from p-NAD+ by ADP-ribosyl cyclases and hydrolyzed to its inactive metabolite, ADP-ribose, by cADPR hydrolases. In mammalian cells, cyclase and hydrolase activities have been shown to be expressed on one bifunctional protein. 

CD38 is a multifunctional protein expressed primarily on lymphoid cells but also in other tissues (Malavasi et al, 1994). It has been shown to be a bifunctional enzyme expressing both ADP-ribosyl cyclase and cADPR hydrolase activities (Howard et al., 1993 Sum-merhill et al., 1993), and has sequence homology with the Aplysia ADP-ribosyl cyclase enzyme (States et al.,... 

ADP-ribosyl cyclase and cADPR hydrolase activities have been shown to be widespread in mammalian and other tissues (see Sections III.B and III.C). However, the demonstration that these enzymes are bifunctional in that they are resident on the same protein has led to the suggestion that many common ecto-NAD" glycohydrolases, which covert NAD+ to ADP-ribose, may do so via cADPR as an intermediate (Kim et al., 1993b). This might suggest that many of these... 

Since muscle cells contain the highest densities of RyRs and cADPR levels and ADP-ribosyl cyclase activities have been measured in mammalian heart (Wal-seth etal., 1991), cardiac muscle was an obvious choice in which to investigate the effects of cADPR in mammalian tissues. 

FIGURES Scheme for interactions between smooth muscle cells and nitric oxide-generating cells. NO causes the mobilization of intracellular Ca + in interstitial cells in the mammalian gut. This effect is blocked by ryanodine. The rise in Ca + causes more production of NO by activated NO synthase. The NO produced is released from the cells and penetrates neighboring smooth muscle cells, leading to relaxation. Since, in the sea urchin egg, NO mobilizes Ca - by increasing cGMP, which in turn activates ADP-ribosyl cyclase, it is possible that in interstitial cells, cADPR mediates this effect. 

---