5-Amino-1MQ vs Aicar

5-Amino-1MQ

5-Amino-1MQ is a small quinolinium molecule, not a peptide, designed to inhibit the enzyme nicotinamide N-methyltransferase (NNMT). It came out of medicinal-chemistry work on a series of methylquinolinium analogues screened against that enzyme, which methylates nicotinamide and is expressed at high levels in liver and fat tissue. Interest in NNMT grew once it was linked to the balance of NAD+ and of methyl donors inside cells. Published work on 5-Amino-1MQ is preclinical: enzyme assays, cultured fat cells and diet-induced obese mouse models. Human data are very limited, and its selectivity and behaviour in the whole organism are not well characterised.

Aicar

AICAR, also called acadesine, is 5-aminoimidazole-4-carboxamide riboside: a synthetic nucleoside, not a peptide or an amino-acid derivative. Its monophosphate, ZMP, is a natural intermediate in the pathway cells use to build purine nucleotides. AICAR became a standard laboratory tool because cells convert it to ZMP, which mimics AMP and switches on AMP-activated protein kinase (AMPK). A large body of cell and rodent work has used it to study energy sensing, glucose uptake and fatty-acid metabolism. Human clinical work has been limited and has not centred on metabolism. A known weakness of the tool is that ZMP acts on other AMP-sensitive enzymes too, so not every effect attributed to AICAR runs through AMPK.

How 5-Amino-1MQ acts

NNMT transfers a methyl group from S-adenosylmethionine (SAM) to nicotinamide, producing 1-methylnicotinamide and S-adenosylhomocysteine. 5-Amino-1MQ is thought to occupy the enzyme's nicotinamide site and compete with the natural substrate. Because the reaction consumes both SAM and nicotinamide, a precursor recycled into NAD+ through the salvage pathway, inhibitors of this kind have been used in cultured adipocytes and rodent studies to examine how NNMT activity relates to intracellular NAD+ and SAM levels and to lipid handling in fat cells. How selective the compound is across other methyltransferases, and how it is distributed and cleared in animals, has been only partly described.

How Aicar acts

AICAR enters cells through adenosine transporters and is phosphorylated by adenosine kinase to ZMP. ZMP binds the regulatory gamma subunit of AMPK at sites that normally sense AMP, and this allosteric activation, together with increased phosphorylation of the catalytic alpha subunit, raises the kinase's activity. Activated AMPK phosphorylates targets such as acetyl-CoA carboxylase, shifting cells away from lipid synthesis and toward processes that generate ATP. ZMP accumulates to high concentrations, however, and has been reported to affect other AMP-regulated enzymes, including fructose-1,6-bisphosphatase and glycogen phosphorylase. Studies that need to separate AMPK-dependent effects often pair AICAR with genetic knockout models.

The records side by side

• Type: 5-Amino-1MQ, Small molecule (quinolinium cation); Aicar, Nucleoside analogue
• Molecular weight: 5-Amino-1MQ, 159.21 g/mol; Aicar, 258.23 g/mol
• Molecular formula: 5-Amino-1MQ, C10H11N2+; Aicar, C9H14N4O5

Reading a comparison

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