5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-Monophosphate (AICAR), a Highly Conserved Purine Intermediate with Multiple Effects

Abstract

AICAR (5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate) is a natural metabolic intermediate of purine biosynthesis that is present in all organisms. In yeast, AICAR plays important regulatory roles under physiological conditions, notably through its direct interactions with transcription factors. In humans, AICAR accumulates in several metabolic diseases, but its contribution to the symptoms has not yet been elucidated. Further, AICAR has highly promising properties which have been recently revealed. Indeed, it enhances endurance of sedentary mice. In addition, it has antiproliferative effects notably by specifically inducing apoptosis of aneuploid cells. Some of the effects of AICAR are due to its ability to stimulate the AMP-activated protein kinase but some others are not. It is consequently clear that AICAR affects multiple targets although only few of them have been identified so far. This review proposes an overview of the field and suggests future directions.

Figure 1

Schematic representation of the de novo purine and histidine pathways in yeast. AICAR: 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate. AICAr: riboside form of AICAR (also named acadesine). AMP: Adenosine 5'-monophosphate; GMP: Guanosine 5'-monophosphate; IMP: Inosine 5'-monophosphate. PRFAICAR: 5-(5-Phospho-D-ribosylaminoformimino)-1-(5-phosphoribosyl)-imidazole-4-carboxamide. SAICAR: succinyl-AICAR. SAICAr: succinyl-AICAr. ZMP: AICAR monophosphate. ZTP: AICAR triphosphate. Enzyme names are given in blue. Question marks indicate enzymatic activities catalyzed by unidentified enzymes.

Figure 2

Schematic representation of AICAR physiological effects in yeast. Intracellular ATP and AICAR concentrations were determined by liquid chromatography as described in [19] on exponentially BY4741 cells grown in SD medium containing 1% casaminoacid (Difco), tryptophan (0.2 mM) and containing (upper panel) or not (lower panel) adenine (0.3 mM). ADE and PHO genes refer to Bas1-Pho2 and Pho4-Pho2 target genes, respectively.

Figure 3

Schematic depiction of AICAR cellular targets and associated biological effects.CML: Chronic myeloid leukemia. CLL: Chronic lymphocytic leukemia. PKC: Protein kinase C. Ryr1: Ryanodine receptor 1. All targets and biological effects presented are described in [29,30,31,32,33,34,35,36].