Scientific Reference
AICAR (Acadesine)
Evidence profile: Controlled human evidence
AICAR is the laboratory's standard way of switching on AMP-activated protein kinase, and it earned that position by an accident of chemistry rather than by design. It is 5-aminoimidazole-4-carboxamide riboside, also called acadesine, a synthetic nucleoside with no peptide or amino-acid character at all, and cells phosphorylate it into ZMP, which already exists in them as an intermediate in purine nucleotide synthesis. ZMP resembles AMP closely enough to be read as an energy-depletion signal, which is what makes the compound useful. Cell and rodent studies of energy sensing, glucose uptake and fatty-acid metabolism have relied on it heavily. Human clinical work is limited and has not concentrated on metabolism. The tool has a known flaw worth stating plainly: ZMP is not selective for AMPK, so an effect observed with AICAR is not automatically an AMPK effect.
Mechanism of Action
The compound is carried into cells by adenosine transporters and phosphorylated by adenosine kinase, producing ZMP. ZMP then occupies the AMP-sensing sites on AMPK's regulatory gamma subunit; that allosteric binding, together with increased phosphorylation of the catalytic alpha subunit, lifts the kinase's activity. Among AMPK's substrates is acetyl-CoA carboxylase, and phosphorylating it turns cells away from building lipid and toward making ATP. The complication is concentration: ZMP builds up well beyond physiological AMP levels and has been reported to act on other AMP-regulated enzymes, fructose-1,6-bisphosphatase and glycogen phosphorylase among them. Work that needs a clean answer about AMPK therefore tends to run AICAR alongside genetic knockouts.
Molecular Information
- Type: Nucleoside analogue
- Molecular weight: 258.23 g/mol
- Molecular formula: C9H14N4O5
- CAS: 2627-69-2
Published Research
Urine levels of 5-aminoimidazole-4-carboxamide riboside (AICAR) in patients with type 2 diabetes
Mendler M et al. · Acta diabetologica · 2018 · Clinical
PMID 29546577 — View on PubMed5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men
Cuthbertson DJ et al. · Diabetes · 2007 · Clinical
PMID 17513706 — View on PubMed