Absorption, transport and metabolism of niacin Domina Petric, MD

Absorption of niacin I. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Digestion of NAD/NADP The predominant forms of niacin in most animal derived foods, NAD(H) and NADP(H), appear to be digested to release nicotinamide (NAm), in which form the vitamin is absorbed. Both coenzyme forms can be degraded by the intestinal mucosal enzyme NAD(P)+ glycohydrolase, which cleaves the pyridine nucleotides into NAm and ADP-ribose. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Digestion of NAD/NADP Nicotinamide can also be cleaved at the pyrophosphate bond to yield nicotinamide mononucleotide (NMN) and 5'-AMP, or by a phosphodiesterase to yield nicotinamide riboside (NR) and ADP. The dephosphorylation of NMN also yields NR, which can be converted to NAm either by hydrolysis (yielding ribose) or phosphorylation (yielding ribose 1-phosphate). November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Digestion of NAD/NADP The cleavage of NAm to free nicotinic acid (NA) appears to be accomplished by intestinal microorganisms and is believed to be of quantitative importance in niacin absorption. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Facilitated diffusion Niacin is absorbed in the stomach and small intestine. The rate of diffusion of NA is about half that of NAm. At high concentrations each is absorbed via passive diffusion. At pharmacologic concentrations the vitamin is absorbed nearly completely. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Facilitated diffusion The presence or absence of food in the gut appears to have no effect on niacin absorption. NR is not found in plasma: it appears not to be absorbed per se, but is first converted to NAm. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transport of niacin II. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Free in plasma Niacin is transported in the plasma as both NA and NAm in unbound forms. Because the NA is converted to NAD(H) and subsequently to NAm, in the intestine and liver, circulating levels of NAm tend to exceed those of NA. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Cellular uptake Both NA and NAm are taken up by most peripheral tissues through passive diffusion. Some tissues have transport systems that facilitate niacin uptake. Erythrocytes take up NA by the anion transport system. Renal tubules do so by an Na+-dependent, saturable transport system. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Cellular uptake The brain takes up the vitamin by energy-dependent transport systems. The site of the blood-cerebrospinal fluid barrier, the choroid plexus appears to have separate system for the accumulation/release of NA and NAm. Brain cells also have a high-affinity transport system for NAm. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Cellular uptake These two levels of control effect the homeostasis of niacin in the brain: NAm but not NA enters readily. A high-affinity, G protein-coupled receptor for NA has been identified in adipose tissue. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Tissue storage Niacin is retained in tissues that take it up as NA and/or NAm by being trapped by conversion to the pyridine nucleotides NAD(H) and NADP(H). By far the greater amount is found as NAD(H), most of which, in contrast to NADP(H), is found in the oxidized form (NAD+). November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolism of niacin III. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Niacin biosynthesis Humans are capable, to varying degrees, of the de novo synthesis of the metabolically active forms of niacin, NAD(H) and NADP(H), from quinolinic acid, a metabolite of the indispensable amino acid tryptophan. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Tryptophan-niacin conversion Ring-hydroxylation of kynurenine Oxidative cleavage of the tryptophan pyrrole ring The xanthurenic acid side chain’s cleaving of the amino acid alanine by the pyridoxal phosphate dependent enzyme kynureninase, to yield 3-hydroxyanthranilic acid (3-OH-AA). by tryptophan pyrrolase, which yields N-formylkynurenine. by the FAD-dependent kynurenine 3-hydroxylase to yield 3-hydroxykynurenine (3-OH-Ky) . First step Second step Third step Fourth step Fifth step The removal of the formyl group Deamination of 3-OH-Ky by formylase to form kynurenine. by a zinc-activated enzyme, pyridoxal phosphate-dependent transaminase, to yield xanthurenic acid. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Tryptophan-niacin conversion Sixth step: Oxidative ring-opening of 3-OH-AA by an Fe2+-dependent dioxygenase, 3-hydroxyanthranilic acid oxygenase (3-HAAO), to yield the semistable α-amino-β-carboxymuconic-ε-semi-aldehyde (ACS). November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

ACS is a branch-point intermediate in the pathway: Catabolism to inactive metabolites Conversion to NAD+ ACS can spontaneously cyclize and undergo decarboxylation to yield picolinic acid, or it can be converted by picolinic acid carboxylase (PAC) to α-aminomuconic-ε- semialdehyde, which is reduced and further decarboxylated to yield acetyl-CoA. ACS can spontaneously cyclize to form quinolinic acid (QA), which can be decarboxylated and phosphoribosylated to yield NMN by quinolinate phosphoribosyltransferase. NMN is phosphoadenylated by the ATP-dependent NAD+ synthetase to yield NAD+. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Sources of NAD(H) and NADP(H) The metabolically active forms of niacin, the pyridine nucleotides NAD(H) and NADP(H), are synthesized from three precursors: NA NAm tryptophan November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Conversion efficiency The conversion of tryptophan to NAD is a generally inefficient process. Humans appear normally to convert 60 mg of tryptophan to 1 mg of niacin. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin B6 (pyridoxine) Pyridoxal phosphate-dependent enzymes are involved at four points in the tryptophan-niacin pathway: Two transaminases: which catalyze the conversions of kynurenine to kynurenic acid and of 3-hydroxykynurenine to xanthurenic acid. Kynureninase: which catalyzes the conversion of kynurenine to anthranilic acid as well as that of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin B6 (pyridoxine) The conversion efficiency of tryptophan to niacin is reduced under conditions of pyridoxine deficiency. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Catabolism The pyridine nucleotides are catabolized by hydrolytic cleavage of their two β-glycosidic bonds, primarily the one at the nicotinamide moiety, by NAD(P)+ glycohydrolase. Nicotinamide so released can be deamidated to form NA, in which form it can be reconverted to NAD+. Alternatively, it can be methylated (mainly in the liver) by nicotinamide N-methyltransferase to yield 1-methylnicotinamide, which can be oxidized to a variety of products that are excreted in the urine. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Excretion At typical levels of intake of the vitamin, the major urinary metabolites are: 1-methylnicotinamide oxidation product 1-methyl-6-pyridone-3-carboxamide November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Excretion At high rates of niacin intake, the vitamin is excreted predominantly (65-85% of total) in unchanged form. November 19, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Literature Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. November 19, 2018