The ADP-ribosyl cyclases - the current evolutionary state of the ARCs

Abstract

The major ADP-ribosylating enzyme families are the focus of this special issue of Frontiers in Bioscience. However, there is room for another family of enzymes with the capacity to utilize nicotinamide adenine dinucleotide (NAD): the ADPribosyl cyclases (ARCs). These unique enzymes catalyse the cyclization of NAD to cyclic ADP ribose (cADPR), a widely distributed second messenger. However, the ARCs are versatile enzymes that can manipulate NAD, NAD phosphate (NADP) and other substrates to generate various bioactive molecules including nicotinic acid adenine dinucleotide diphosphate (NAADP) and ADP ribose (ADPR). This review will focus on the group of well-characterized ARCs identified in invertebrate and vertebrate animals, whose common gene structure allows us to trace their origin to the ancestor of bilaterian animals. Behind a façade of gene and protein homology lies a family with a disparate functional repertoire dictated by the animal model and the physical trait under investigation. Here we present a phylogenetic view of the ARCs to better understand the evolution of function in this family. Eggs, this "rich source for experimentation" have been a cornucopia for the ARCs. It was in the egg of the sea urchin Lytechinus pictus that cADPR was first identified as a mediator of stimulus-induced calcium release (2). It was another invertebrate egg, that of the sea slug Aplysia californica, that gave us the first enzyme capable of cADPR biosynthesis (3). Here is the story in brief. INTRODUCTIONThe excitement began just over 25 years ago when it first emerged that NAD, NADP and then cADPR could trigger Ca 2+ release in eggs of the sea urchin Lytechinus pictus (4), on a par with inositol-1,4,5-trisphosphate (InsP3) (5), until then one of the most potent intracellular messengers. Although the capacity to synthesize cADPR and mobilize Ca 2+ was shown to be quite broadly distributed in animal tissues (6), the enzyme responsible for converting NAD to cADPR remained unknown. By a classic 2 stroke of serendipity, the enzyme was detected by scientists studying ADP-ribosylation of G-proteins by the bacterial cholera and diptheria exotoxins in the marine gastropod mollusc Aplysia californica (7). ADP-ribosylation occurred in all examined tissues, except in the ovotestis. The unexpected finding was intelligently pursued until the 'inhibitory factor' was characterized as a NADsplitting protein capable of producing cADPR, similar to the enzymatic activity first identified in sea urchin eggs. This first ARC was molecularly cloned (8) and called 'ADP-ribosyl cyclase' in 1991 by Lee and Aarhus to avoid confusion with other NAD glycohydrolases (EC 3.2.2.5) (3). As will be discussed below, the antagonism between the mono-ADP-ribosyltransferases (mART) and the ARCs revealed in molluscan eggs is probably just the tip of the iceberg of this phenomenon. In the meantime, the availability of an amino acid sequence enabled the sequence homology-based identification of ARCs in other species, first amongst these, human CD38 (9). THE...

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