Transport and cellular uptake

Blood circulation: The main vitamers transported in blood are nicotinate and nicotinamide. An as yet incompletely characterized anion transporter facilitates diffusion of NAD into red blood cells, and possibly other tissues.

NAD also exchanges between adjacent cells. Connexin 43 (C\43). a component of intercellular gap junctions, functions as an NAD transporter that facilitates diffusion between cells (Bruzzone et ul., 20(11 i

Blood -brain barrier: Both nicotinamide and nicotinate are transported rapidly into brain, as demonstrated by PET scans (Ha tikes et a!.. 1991). Nicotinamide transfer may be more efficient ihan nicotmatc transfer, but the underlying mechanisms are not well understood.

Matemo-fetal transfer: Transport of niacin derivatives across the placenta is a necessity, since the fetus depends on this vitamin, just like the mother. Nicotinate. however, does not appear to cross easily (Baker et ul.. 19X1 ( and other forms may be more important for transfer to the fetus.

Metabolism

Nucleotide synthesis: NAD and NADP are readily synthesized from nicotmatc or nicotinamide, or from L-tryptophan-derived nicotinate mononucleotide. Synthesis takes place in liver, red blood cells, and other tissues,

Nicotinate mononucleotide may be considered the starling point of the predominant pathway (Preiss Handler pathway) in liver and red blood cells. This intermediate is produced largely from nicotinate by nicotinate phosphoribosy¬°transferase (EC2.4.2.11, magnesium-dependent). Nicotinate, in turn, may have been generated from nicotinamide through the action of mcotinamidase (EC3.5.L19. magnesium-dependenl>. Only a much smaller percentage comes from I.-tryptophan eatabolism. Addition of adenosine phosphate by magnesium-dependent nicotinate-nucleotide adenyly I transferase (F.C2.7.7.18, Sehwciger et ul., 2001) generates deaniido-NAD. The gltttamine-hydrolyzing NAD synthase (EC6.3.5.I) can use either the amino group from glutamine or ammonium ions. Lead exposure inhibits the activ ity of this enzyme in red blood cells (Morita et ul.. 1997). Even modestly elevated blood lead levels (<60()jigl) diminish NAD synthase activity by two-thirds compared to low lead levels (* 200jj.g/l). NADP is produced through additional phosphorylation of NAD by NAD kinase (EC2.7.1.231.

Equally important is NAD synthesis directly from nicotinamide in just two steps (Dietrich pathway), which occurs in red and white blood cells as well as in other tissues. Nicotinate phosphoribosy I transferase (EC2.4.2.11) tirsi links phosphoribosyl pyrophosphate to nicotinamide. The next and final step can then be catalyzed by nicotinamide-nucleotide adenylyltransferase (EC2.7.7.I).

ADP ribose synthesis: Endocytotic vesicles have the ability to generate cyclic ADP ribose (ADPR). First a distinct dinucleotide transport system imports NAD from cytosol (Zoechi et ul.. 1999). NAD hydrolysis by NAD nucleosidase (EC3.2.2.5) then generates ADPR.

Breakdown: Nicotinamide can be converted to N-methy(nicotinamide (NMN) by nicotinamide N-methy(transferase (EC2,LI.I >. The use of S-adenosyl-L-methionine (SAM) as the methyl group donor generates S-adenosyl-L-homocysteine (SAH) and links the reaction to adequate availability of folate and vitamin B12. This reaction metabolicatly sequesters excessive amounts of nicotinamide, especially in the liver.

Synthesis from L-Tryptophan

Food

Food

Nicotinic acid

OH OH rocamWe kinase -s

Nicotinamide

Nicotinic acid

pyrophos- k 0H phorylase 1 " PP,

OH OH rocamWe kinase -s

Nicotinamide

Adenosine diphospho-ribose

o pyrophos- k 0H phorylase 1 " PP,

OH OH Phosphoribosyl pyrophosphate (PRPP)

OH OH Nicotinate mononucleotide Nicotinate nucleotide adenylyl-t ran sie rase (magnesium)

Adenosine diphospho-ribose

r

ATP

PP,

H

0

-‚ÄĘc OH

OH OH Nicotinamide mononucleotide ADP

Nicotinamide nucleotide adenytyt-transf erase

H2 N

O OH OH

Glutamine Gl Uta- h0-P=0 or NH3 mate | H

NAD synthase

OH OH Nicotinamide mononucleotide ADP

Nicotinamide nucleotide adenytyt-transf erase

Glutamine Gl Uta- h0-P=0 or NH3 mate | H

OH OH Nicotinamide adenine dinucleotide (NAD)

OH OH Deamido NAD

Figure 10.20 Metabolism of niacin compounds

OH OH Nicotinamide adenine dinucleotide (NAD)

Aldehyde oxidase (EC 1.2.3.1, contains molvbdopterin and heme) can metabolize NMN further to Nl-methyl-2-pyridone-5-carboxamide or N l-methyl-4-pyridone-3-carboxamide. Nicotinuric acid is a major metabolite of nicotinate that arises from its conjugation to glycine (catalyzed by glycine N-benzoyltransfcrase, EC2.3.L71, and/or glycine N-acyl transferase. EC2.3.I.I3). especially when a pharmacological dose of nicotinate is ingested (Neuvonen ei a!.. 1991).

Nicolinamidase (magnesium!

Nicolinamidase (magnesium!

O II

NH? SAM SAH

Nicotinic acid

Glycine N-benzoyl -trans! era se

Nicotinamide N-m ethyl transferase

NH? SAM SAH

Nicotinamide N-m ethyl transferase

Nicotinamide

N1 -metbylnicotinamide

Nicotinic acid

Glycine N-benzoyl -trans! era se

nucleosidase

Deamido NAD

Nicotin ate mononucleotide

Figure 1D.21 Catabotism of niacin compounds

nucleosidase

Adenosine diphospho-ribose

Aldehyde oxidase (molybdopterin and heme)

Deamido NAD

0 II

Nicotin ate mononucleotide

Nt-methyl-4- u N pyndone-3-carboxamide

Nicotinuric acid

Figure 1D.21 Catabotism of niacin compounds ch3 N1-methyi-2-pyridone-5-carboxamide

Niacin salvage pathways: NAD. NADP. and related metabolites arc recycled extensively,

Extracellular NAD can be broken down by NAD nucleosidase (NAD-glycohydrolase. EC.3,2.2.5). which releases nicotinamide and ADP-ribose (ADPR), or by nucleotide pyrophosphatase {EC3.6.1.9), which releases nicotinamide mononucleotide (NMN) and AMP. Both enzymes are active on the external lace of cell membranes (Aleo et ni, 20(11 ). NAD and NADP arc readily resyntliesized from these products bj lite pathways described earlier. \\ heiher humans have additional salvage reactions, which are known to be of importance in bacteria (Magni el til.. 1990). remains to be seen. Salvage reactions operating in these organisms include NAD and NADU pyrophosphatases (EC3.fi.L22. generate MNM). nicotinamide deamidase, and NMN dcamidasc.

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