This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Enzymes that cleave the nicotinamide-ribosyl bond have been observed in all forms of life. Of particular interest is the ADPRibosyltransferases (ARTs). This group of enzymes was first identified as bacterial toxins responsible for the symptoms of cholera, pertussis and diphtheria. More recently ARTs were identified on the surface of vertebrate cells from mice, rats, turkeys and humans, and sequence analysis established them to be evolutionarily related to the bacterial toxins. In this study we propose to investigate the relationship among other ARTs and NAD-glycohydrolases (NADases) as to their evolutionary relationship and cellular function. We propose to establish the presense or absence of ARTs from other organisms including plants, fungi, and invertebrates. We will also determine the sequences of other NADases and analyze their evolutionary relationship with other enzymes that cleave the nicotinamide-ribosyl bond. The foucs of this proposal is to determine the origin of the ARTs as a regulatory system in vertebrates and how a pathogenic toxin can be remolded into a system important to the maintenance of life. From this insight we will better undertand the functions of ARTs in vertebrates.
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