Aarhus R, Graeff R M, Dickey D M, Walseth T F, Lee H C
Department of Physiology, University of Minnesota, Minneapolis 55455, USA.
J Biol Chem. 1995 Dec 22;270(51):30327-33. doi: 10.1074/jbc.270.51.30327.
ADP-ribosyl cyclase catalyzes the cyclization of NAD+ to produce cyclic ADP-ribose (cADPR), which is emerging as an endogenous regulator of the Ca(2+)-induced Ca2+ release mechanism in cells. CD38 is a lymphocyte differentiation antigen which has recently been shown to be a bifunctional enzyme that can synthesize cADPR from NAD+ as well as hydrolyze cADPR to ADP-ribose. In this study, we show that both the cyclase and CD38 can also catalyze the exchange of the nicotinamide group of NADP+ with nicotine acid (NA). The product is nicotinic acid adenine dinucleotide phosphate (NAADP+), a metabolite we have previously shown to be potent in Ca2+ mobilization (Lee, H. C., and Aarhus, R. (1995) J. Biol. Chem. 270, 2152-2157). The switch of the catalysis to the exchange reaction requires acidic pH and NA. The half-maximal effective concentration of NA is about 5 mM for both the cyclase and CD38. In the absence of NA or at neutral pH, the cyclase converts NADP+ to another metabolite, which is identified as cyclic ADP-ribose 2'-phosphate. Under the same conditions, CD38 converts NADP+ to ADP-ribose 2'-phosphate instead, which is the hydrolysis product of cyclic ADP-ribose 2'-phosphate. That two different products of ADP-ribosyl cyclase and CD38, cADPR and NAADP+, are both involved in Ca2+ mobilization suggests a crucial role of these enzymes in Ca2+ signaling.
ADP-核糖基环化酶催化NAD⁺环化生成环ADP-核糖（cADPR），cADPR正逐渐成为细胞中钙诱导钙释放机制的内源性调节剂。CD38是一种淋巴细胞分化抗原，最近已被证明是一种双功能酶，它既能从NAD⁺合成cADPR，也能将cADPR水解为ADP-核糖。在本研究中，我们发现环化酶和CD38都还能催化NADP⁺的烟酰胺基团与烟酸（NA）进行交换。产物是烟酸腺嘌呤二核苷酸磷酸（NAADP⁺），我们之前已证明这种代谢物在钙动员方面具有强大作用（Lee, H. C., and Aarhus, R. (1995) J. Biol. Chem. 270, 2152 - 2157）。催化反应转换为交换反应需要酸性pH和NA。对于环化酶和CD38，NA的半数有效浓度约为5 mM。在没有NA或中性pH条件下，环化酶将NADP⁺转化为另一种代谢物，经鉴定为环ADP-核糖2'-磷酸。在相同条件下，CD38则将NADP⁺转化为ADP-核糖2'-磷酸，而ADP-核糖2'-磷酸是环ADP-核糖2'-磷酸的水解产物。ADP-核糖基环化酶和CD38的两种不同产物cADPR和NAADP⁺都参与钙动员，这表明这些酶在钙信号传导中起着关键作用。
