cADPR
https://en.wikipedia.org/wiki/Cyclic_ADP-ribose
ADPR
NAADP (inhibiittori: diltiatsedm, dihydropyridiini)
NAAD
NADH
https://en.wikipedia.org/wiki/Nicotinic_acid_adenine_dinucleotide_phosphate
https://www.researchgate.net/figure/Mammalian-NAD-metabolic-pathways-The-biosynthesis-of-
Mammalian NAD metabolic pathways. The biosynthesis of NAD occurs through both de novo and salvage pathways (339). In mammalian cells, 90% of free tryptophan is metabolized through the kynurenine pathway, leading to the de novo synthesis of NAD. The three different salvage pathways start either from nicotinamide (Nam), nicotinic acid (Na), or nicotinamide riboside (NR). In mammals, the origin of nicotinic acid is mainly nutritional. Nicotinamide, a product of NAD hydrolysis, is first converted into nicotinamide mononucleotide (NMN) and then into NAD by nicotinamide phosphoribosyl transferase (NamPRT) and nicotinamide mononucleotide adenylyl transferases (Na/NMNAT-1,-2, and-3), respectively. Nicotinamide riboside was recently shown to serve as a precursor for NAD synthesis, connected to the Nam salvage pathway through NMN (36). Nicotinamide riboside is converted to NMN by the ATP-consuming nicotinamide riboside kinases 1 and 2 (NRK-1 and-2) (36). Nicotinic acid can be converted through the Preiss-Handler salvage pathway into nicotinic acid mononucleotide (NaNM) and nicotinate adenine dinucleotide by the concerted actions of nicotinic acid phosphoribosyl transferase (NaPRT) and Na/NMNAT-1,-2, and-3, respectively. Nicotinate adenine dinucleotide is directly transformed into NAD by the glutamine-hydrolyzing NAD synthetase (NADS). Na/NMNATs are ATP-consuming enzymes, using either NaMN or NMN as a substrate. Whether both NamPRT and NaPRT are also ATPconsuming enzymes in vivo is not certain. Thus, when the Preiss-Handler salvage pathway is used, the cell invests three or four molecules of ATP from Na to NAD , depending on whether NaPRT is also an ATP-consuming enzyme in vivo. In mammalian cells, under the conditions where NAD is used as a glycohydrolase substrate, the Nam salvage pathway is required, since there is no nicotinamidase to produce nicotinic acid. Depending on whether NamPRT uses one ATP molecule to convert Nam into NMN, the Nam salvage pathway consumes two or three ATP molecules from Nam to NAD. The de novo pathway is connected to the Preiss-Handler salvage pathway through NaMN. NAD can be hydrolyzed by various enzymatic activities, such as PARPs, MARTs, SIRTs, and ADP-ribosyl cyclases, which release the Nam moiety from NAD to produce poly-ADP-ribose, mono-ADP-ribosyl-protein, acetyl-ADP-ribose (O-AADPR), or cyclic-ADP-ribose (cADPR) and nicotinate adenine dinucleotide phosphate (NAADP), respectively. These products are then further metabolized by different hydrolase activities, yielding ADP-ribose (ADPR), which, in turn, can be transformed into 5-phosphribosyl-1-pyrophosphate (PRPP) by the ATP-consuming ADP-ribose pyrophosphatase (ARPP)/ribose phosphate pyrophosphokinase (RPPK) pathway. PRPP is used by the Nam salvage pathway enzymes NamPRT and NaPRT.
NAD-occurs-through-both-de-novo-and_fig1_6830373https://www.researchgate.net/publication/235895284_Macrodomain-containing_proteins_are_new_mono-ADP-ribosylhydrolases..
Abstract
ADP-ribosylation
is an important post-translational protein modification (PTM) that
regulates diverse biological processes. ADP-ribosyltransferase
diphtheria toxin-like 10 (ARTD10, also known as PARP10)
mono-ADP-ribosylates acidic side chains and is one of eighteen
ADP-ribosyltransferases that catalyze mono- or poly-ADP-ribosylation of
target proteins. Currently, no enzyme is known that reverses
ARTD10-catalyzed mono-ADP-ribosylation. Here we report that
ARTD10-modified targets are substrates for the macrodomain proteins
MacroD1, MacroD2 and C6orf130 from Homo sapiens as well as for the
macrodomain protein Af1521 from archaebacteria. Structural modeling and
mutagenesis of MacroD1 and MacroD2 revealed a common core structure with
Asp102 and His106 of MacroD2 implicated in the hydrolytic reaction.
Notably, MacroD2 reversed the ARTD10-catalyzed, mono-ADP-ribose-mediated
inhibition of glycogen synthase kinase 3β (GSK3β) in vitro and in
cells, thus underlining the physiological and regulatory importance of
mono-ADP-ribosylhydrolase activity. Our results establish
macrodomain-containing proteins as mono-ADP-ribosylhydrolases and define
a class of enzymes that renders mono-ADP-ribosylation a reversible
modification.
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SvaraRaderaNicotinamide mononucleotide