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2.
Fig. 1

Fig. 1. The SIRT1-catalyzed protein deacetylation reaction. From: SIRT1-dependent Regulation of Chromatin and Transcription: Linking NAD+ Metabolism and Signaling to the Control of Cellular Functions.

NAD+ is consumed as a substrate for the deacetylation of target proteins, which are acetylated on specific lysine (Lys) residues. The products in the reaction are deacetylated protein, nicotinamide (NAM), and O-acetyl-ADP-ribose (OAADPR).

Tong Zhang, et al. Biochim Biophys Acta. ;1804(8):1666-1675.
3.
Fig. 6

Fig. 6. Cross-talk between SIRT1 and PARP-1 in stress responses. From: SIRT1-dependent Regulation of Chromatin and Transcription: Linking NAD+ Metabolism and Signaling to the Control of Cellular Functions.

Stress activates PARP-1 through DNA damage and acetylation of PARP-1. Poly(ADP-ribosyl)ation by PARP-1 markedly reduces cellular NAD+ levels and increases NAM levels, leading to inhibition of SIRT1 activity. Together, these changes can lead to apoptotic or necrotic cell death. To counteract the action of PARP-1, SIRT1 interacts with and deacetylates PARP-1 when NAD+ levels are low, thereby inhibiting PARP-1 activity. This function of SIRT1 helps to maintain cellular NAD+ levels and SIRT1 activity, and promotes cell survival in response to stress. Ac-ADPR, acetylated ADP-ribose or OAADPR.

Tong Zhang, et al. Biochim Biophys Acta. ;1804(8):1666-1675.
4.
Fig. 3

Fig. 3. Mammalian NAD+ biosynthetic pathways. From: SIRT1-dependent Regulation of Chromatin and Transcription: Linking NAD+ Metabolism and Signaling to the Control of Cellular Functions.

In mammals, NAD+ can be synthesized through two pathways. The de novo pathway uses L-tryptophan as the precursor for NAD+ production in a multi-step pathway. The salvage pathway uses nicotinamide or nicotinic acid (together called niacin or vitamin B3) to make NAD+. In addition, nicotinamide riboside has been identified as a dietary precursor for NAD+ biosynthesis. QPRTase, quinolinic acid phosphoribosyltransferase; NPT, nicotinic acid phosphoribosyltransferase; NMNAT, nicotinamide/nicotinic acid mononucleotide adenylyltransferase; NAMPT, nicotinamide phosphoribosyltransferase; NADS, NAD synthase, NRK, nicotinamide riboside kinase.

Tong Zhang, et al. Biochim Biophys Acta. ;1804(8):1666-1675.
5.
Fig. 5

Fig. 5. Regulation of SIRT1 activity at target gene promoters by nuclear NAD+- producing enzymes. From: SIRT1-dependent Regulation of Chromatin and Transcription: Linking NAD+ Metabolism and Signaling to the Control of Cellular Functions.

SIRT1 is recruited to target gene promoters and regulates the acetylation state of histones, transcription factors, and other chromatin-associated proteins in an NAD+-dependent manner. Nicotinamide (NAM), a byproduct of SIRT1-catalyzed deacetylation reactions, is a potent inhibitor of SIRT1 activity. NAMPT and NMNAT-1 constitute a nuclear NAD+ recycling pathway that utilizes NAM for NAD+ biosynthesis. NAM removal and NAD+ production by NAMPT and NMNAT-1 stimulate SIRT1 activity in the nucleus. In addition, NMNAT-1 interacts with SIRT1 and is recruited to SIRT1 target gene promoters. SIRT1-dependent recruitment of NMNAT-1 to chromatin may produce NAD+ for direct shuttling to SIRT1 to support its activity. TF, transcription factor. Ac, acetyl group.

Tong Zhang, et al. Biochim Biophys Acta. ;1804(8):1666-1675.
6.
Fig. 4

Fig. 4. Feedback regulation of circadian clock gene expression. From: SIRT1-dependent Regulation of Chromatin and Transcription: Linking NAD+ Metabolism and Signaling to the Control of Cellular Functions.

The circadian rhythm in mammals is controlled by internal “clocks” that temporally regulate biological functions in response to environmental and physiological cues in a process that involves negative feedback regulation of gene expression. Many of the core clock proteins are DNA-binding transcription factors, including: CLOCK (a protein acetyltransferase) and BMAL1 (a heterodimerization partner of CLOCK). CLOCK:BMAL1 heterodimers promote the expression of the genes encoding NAMPT, Period (PER) and Cryptochrome 1 (CRY1) through the CLOCK-dependent acetylation of histones and transcription factors (green arrows; Ac, acetyl groups covalently linked to proteins). PER and CRY1 form heterodimers that inhibit CLOCK:BMAL1-dependent transcription. Since the gene encoding NAMPT is a direct target for regulation by CLOCK:BMAL1 heterodimers, NAMPT expression and cellular NAD+ biosynthesis are subject to circadian regulation and exhibit circadian oscillations. Increased NAMPT-dependent NAD+ production enhances SIRT1 deacetylase activity, which acts to inhibit the transcription of NAMPT through interactions with the CLOCK:BMAL1 complex at the NAMPT promoter, thus completing a feedback loop involving NAMPT/NAD+/SIRT1 and CLOCK:BMAL1.

Tong Zhang, et al. Biochim Biophys Acta. ;1804(8):1666-1675.

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