Disease relevance of PNC1

• Here we establish that the so-called NADsyn2 is simply ammonia-dependent NAD+ synthetase from Pseudomonas, which is encoded on an operon with nicotinic acid phosphoribosyltransferase and, in some Pseudomonads, with nicotinamidase [1].
• N-terminal microsequencing revealed sequence identity with a hypothetical polypeptide encoded by the yeast YGL037C open reading frame sharing 30% sequence identity with Escherichia coli pyrazinamidase/nicotinamidase [2].

High impact information on PNC1

• We provide evidence that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity [3].
• Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress [3].
• Furthermore, PNC1 overexpression suppresses the inhibitory effect of exogenously added NAM on silencing, life span, and Hst1-mediated transcriptional repression [4].
• Pnc1 is a nicotinamidase that converts NAM to nicotinic acid [4].
• Additional copies of the salvage pathway genes, PNC1, NMA1, and NMA2, increase telomeric and rDNA silencing, implying that multiple steps affect the rate of the pathway [5].

Biological context of PNC1

• Using a P(PNC1)::lacZ gene fusion, we have shown that this stimulation of NAMase activity results from increased levels of the protein and requires stress response elements in the 5'non-coding region of PNC1 [2].

Associations of PNC1 with chemical compounds

• However, silencing in the absence of PNC1 was completely dependent on the import of nicotinic acid from the growth medium [6].
• We propose a model in which two components of the NAD(+) salvage pathway, Pnc1p and Npt1p, function together in recycling the nuclear nicotinamide generated by Sir2p deacetylase activity back into NAD(+) [6].
• Isonicotinamide also substantially increases transcriptional silencing at Sir2-regulated loci in wt strains and in strains lacking key NAD+ salvage pathway enzymes (PNC1 and NPT1) [7].
• In wild-type strains, NAMase activity is stimulated during the stationary phase of growth, by various hyperosmotic shocks or by ethanol treatment [2].
• Nicotinamidase (NAMase) from the budding yeast, Saccharomyces cerevisiae, was purified by Ni(2+) affinity chromatography and gel filtration [2].

Regulatory relationships of PNC1

• Nicotinamide clearance by Pnc1 directly regulates Sir2-mediated silencing and longevity [4].

Other interactions of PNC1

• Fewer changes were observed during the third generation but certain stress-response proteins such as Hsp26p, Ssa4p and Pnc1p exhibited constitutive expression in subsequent generations [8].

References