NS 3310 Lecture 21

Niacin is the generic term used to describe all forms of niacin found in food, which includes what three things?

1. Nicotinic acid

2. Nicotinamide

3. Nicotinamide riboside

Niacin is a precursor for the endogenous formation of what type of coenzymes? What are two examples?

pyridine nucleotide coenzymes

1. nicotinamide adenine dinucleotide [NAD]

2. Nicotinamide adenine dinucleotide phosphate (NADP)

Niacin vitamers are widely distributed in foods: Niacin and its coenzyme derivatives (NAD, NADP) are naturally found in both?

animal and plant products

Food preparation affects the availability of niacin. How does milling of grain affect niacin? Enriched cereal-grain products contain added?

1. milling of grain removes the bran and germ, which contains thiamin and other B vitamins

2. nicotinamide

Tryptophan is catabolized into a niacin vitamer: Catabolism of tryptophan in the liver results in the formation of nicotinate mononucleotide (small amount), which is used to make NAD or NADP. Tryptophan (60 mg) (meat, milk, and eggs) can be converted to? Which is an?

niacin (1 mg) and is an important source of niacin (despite the inefficiency of the pathway)

How much does tryptophan provide of the niacin needed to meet human requirements (~16mg)?

2/3s

Food preparation affects the bioavailability of niacin: Niacin is fairly stable, with minimal losses of the resulting resulting from what two things?

cooking

storage

~ 70 % of niacin found in corn is biologically unavailable. What increases its bioavailability?

Alkaline treatment

Absorption of niacin occurs via what two diffusions?

1. Passive

2. Facilitated

Absorption of niacin (in its different forms) occurs by? at high intake levels, it can enter the? by passive diffusion

1. passive diffusion in the stomach

2. intestinal cells

Niacin is also absorbed in the small intestine by what process?

a sodium-dependent saturable process

Once in plasma, niacin enters the cells by? that is followed by?

active or passive diffusion

metabolic trapping as NAD or NADP

To fulfill its metabolic roles, niacin is incorporated into? Which can be phosphorylated to form?

NAD+ (the oxidized form of NAD)

NADP+ (the oxidized form of NADP)

Nicotinic ACID metabolism to NAD+: Step one: Nicotinic acid (NA) is converted to nicotinic acid mononucleotide (NMN) by?

NAPRT (nicotinic acid phosphoribosyltransferase)

Nicotinic acid metabolism to NAD+: Step two: NMN is adenylated to form? in an ___ dependent reaction that is catalyzed by?

NaAD

Atp

NMNAT (nicotinamide mononucleotide adenylyltransferase)

Nicotinic acid metabolism to NAD+: Step three: . NaAD is converted to NAD+ by? Which transfers?

NADS (NAD synthetase)

transfers the amide from glutamine to NaMN

NICOTINAMIDE metabolism to NAD+: Step one: What catalyzes the conversion of nicotinamide to NMN?

NAMPT (nicotinamide phosphoribosyltransferase

NICOTINAMIDE metabolism to NAD+: Step two: NMN is converted to NAD+ in an ____ manner, a reaction catalyzed by?

ATP-dependent; NMNAT (nicotinamide mononucleotide adenylyltransferase)

NICOTINAMIDE RIBOSIDE metabolism to NAD+: Step one: Nicotinamide riboside is converted to NMN by?

NRK (nicotinamide riboside kinase)

NICOTINAMIDE RIBOSIDE metabolism to NAD+: Step two: NMN is then converted to NAD+ by?

NMAT

Nicotinamide phosphoribosyltransferase (NAMPT) is regulated to production inhibition; what does this mean?

Nicotinamide phosphoribosyltransferase (NAMPT) is inhibited by NAD+

NAMPT is regulated by product inhibition and thus, which form of niacin has a greater capacity to provide NAD?

Nicotinic acid

Most NAD+ from nicotinic acid, nicotinamide, and nicotinamide riboside is recycled in what type of pathway?

Salvage pathway, a mechanism to maintain cellular NAD+ levels

What is the product left when an NAD+ molecule is consumed?

Niacinamide (NAM)

NAM can be recycled through its conversion into? which catalyzes the?

nicotinamide mononucleotide (NMN) by NAMPT

the rate-limiting reaction in the salvage pathway.

NAM can be recycled through its conversion into nicotinamide mononucleotide (NMN) by NAMPT, which catalyzes the rate-limiting reaction in the salvage pathway. Ultimately, NMN is adenylated by? to yield?

NMNAT; NAD+

Tryptophan metabolism to NAD+; The majority of Trp is used for?

protein synthesis

Which of the following metabolic pathways is FALSE?

T or F: The transformation of nicotinic acid to NAD is regulated through product inhibition.

FALSE

Role of niacin inside cells: Niacin (B3) is used by over 400 different proteins. NAD as a co-enzyme: • NAD and NADP are indispensable in what type of reactions? involved in the catabolism of what 4 things?

oxidation-reduction reactions

1. Glucose

2. Fatty acids

3. ketone bodies

4. amino acids

NAD and NADP are coupled to what type of transfer systems?

electron to oxygen

These coenzymes are coupled to elector-to-oxygen transfer systems, which are the terminal connections between? and are essential for what type of reactions?

1. Energy-yielding metabolic events involving molecular oxygen

2. Reductive biosynthetic reactions

Niacin can also serve as a substrate for what three things?

1. Survival pathways

2. DNA Damage response

3. Second messenger signaling

Survival pathways: NAD is a substrate for? which is a family of deacetylases involved in?

sirtuins; cell survival and longevity

DNA Damage Response: NAD+ acts as a donor of ADP ribose moieties in a process mediated by a family of?

DNA repair enzymes called poly ADPribose polymerases (PARPs).

Second messenger signaling: NAD also participates in what type of signaling events? through?

calcium signaling events through ADP ribosyl-cyclases, including CD38 and SARM1.

Niacin: Redox reactions: Niacin coenzymes participate in oxidation-reduction reactions The nicotinamide component of NAD/NADH and NADP/NADPH undergoes what two processes?

addition (reduction) or loss (oxidation) of hydrogen atoms and their electrons

Niacin: Redox reactions: In healthy cells, the NAD pool is maintained in a highly ___ state mainly by the action of the?

oxidized state (~90% NAD+); electron transport chain

Niacin: Redox reactions: Conversely, the NADP pool is maintained in a highly ____ state, mainly by the action of the?

reduced (NADPH); pentose phosphate pathway.

Enzymes linked to NAD+ become strongly? whereas those linked to NADPH become strongly?

oxidizing; reducing

NAD+ is used as an electron ____for redox reactions involved in the catabolism of____

acceptor; macronutrients

NAD+ is used as an electron acceptor for redox reactions involved in the catabolism of macronutrients; In catabolic pathways, the oxidation of macronutrients is coupled with the reduction of NAD+. NAD+ accepts what two things? as it becomes reduced to?

hydrogen ion (H+ ) and two electrons (2e− ), as it becomes reduced to NADH

NAD+ is used as an electron acceptor for redox reactions involved in the catabolism of macronutrients: The NADH moves to the ____ and donates a pair of electrons (becomes oxidized) to the first compound in the chain to generate?

ETC; ATP

NADPH is used as an electron donor for redox reactions in the synthesis of?

macromolecules

NADPH is used as an electron donor for redox reactions in the synthesis of macromolecules: In anabolic pathways, the oxidation of ____ provides electrons needed for the biosynthesis of?

NADPH; macromolecules

In anabolic pathways, the oxidation of NADPH provides electrons needed for the biosynthesis of macromolecules; NADPH donates?

electrons and becomes oxidized (NADP+ )

NAD+ can be used as substrate for reactions linked to what 3 things which are all affected by niacin/NAD+ supply

1. DNA repair (PARPs)

2. Life extension (sirtuins)

3. Calcium signaling ((ADP ribosylcyclases)

There are seven mammalian sirtuins (SIRT1 - SIRT7), all which are NAD+-dependent enzymes. They function as cellular stress sensors to?

modify histones and a plethora of other proteins-including transcription factors-to modulate diverse cellular processes

There are seven mammalian sirtuins (SIRT1 - SIRT7), all which are NAD+-dependent enzymes. They function as cellular stress sensors to modify histones anda plethora of other proteins-including transcription factors-to modulate diverse cellular processes. What are 4 processes?

1. Energy metabolism

2. Cellular stress responses

3. Genomic stability

4. Tumorigenesis

Promoters of longevity and healthy aging Maintains transcriptional silencing at what 3 things?

1. mating-type loci

2. telomeres,

3. ribosomal DNA arrays.

Protectors from chronic disease NAD-mediated activation of sirtuins has therapeutic benefits in animal models of what two conditions?

1. T2DM

2. Neurodegeneration (presumably by influencing gene expression)

A large body of evidence now supports the physiological roles of sirtuins in suppressing?

aspects of metabolic syndrome, with the potential to affect other age-related diseases such as cancer.

NAD+ as a substrate for PARP enzymes: PARP enzymes [poly(ADP-ribose) polymerases] use NAD+ to generate?

ADP-ribose (generated when nicotinamide is cleaved from NAD+)

PARP enzymes [poly(ADP-ribose) polymerases] use NAD+ to generate ADP-ribose (generated when nicotinamide is cleaved from NAD+), which can be added to?

DNA repair enzymes to increase their activity and reduce DNA damage.

NAD-mediated activation of PARP enzymes has therapeutic benefits in?

cancer and healthy aging

PARP-1 and PARP-2 are activated by? PARPS catalyze the transfer of ADP-ribose to target proteins, essential for recruiting intermediates for the?

DNA damage

DNA repair pathway

T or F: Niacin deficiency could impair the regulation of gene expression.

True

T of F: Niacin deficiency could impair ATP synthesis.

True

All the following statements about niacin are true, EXCEPT:

Niacin deficiency results in?

pellagra,

• was the most devastating vitamin deficiency in US history and was linked to the milling of grains (removes bran and germ) and corn-based diets (bound tryptophan).

Pellagra was particularly rampant in where?, where diets frequently consisted of corn (bound tryptophan), molasses, and biscuits (made from refined flour)

southern US

• Enrichment of refined cereal grains with niacin (along with thiamin, riboflavin, and iron) was mandated in the early 1940s.

Pellagra involves the malfunction of systems that use its?

NAD coenzyme (e.g., redox reactions, PARPs, sirtuins)

An inability to absorb niacin (vit b3) or the aa trp may cause pellagra, a disease characterized by?

scaly sores

mucosal changes

mental symptoms

Pellagra has common causes like?

gastrointestinal diseases, weight loss (bariatric) surgery, anorexia, excessive alcohol use, and drugs (e.g., chloramphenicol

What are 4 symptoms of pellagra? what are the treatments?

Symptoms: Dermatitis, Diarrhea, Dementia, and Death.

Tx: Niacin supplements.

Nicotinic acid has been used to treat?

dyslipidemia

Nicotinic acid has been used to treat dyslipidemia Pharmacological doses of what form of niacin are vert effective in normalizing blood lipid levels (increases in HDL, decreases in LDL, decreases in TAGs).

nicotinic acid (but not nicotinamide)

The activation of HCA (GPR109A) in skin cell capillaries induces strong?

vasodilation leading to the “niacin flush”.

Nicotinic acid has been used to treat dyslipidemia: The high dose niacin effect on lipid abnormalities occurs in part through activation of the high-affinity nicotinic acid?

G protein-coupled receptor (GPR) 109A

The high dose niacin effect on lipid abnormalities occurs in part through activation of the high-affinity nicotinic acid G protein-coupled receptor (GPR) 109A. Activation of this receptor in adipose tissue decreases? and inhibits? which ultimately exerts some beneficial effects on lipid parameters.

decreases cAMP and inhibits lipolysis (PKA is not activated)

Nicotinic acid has been used to treat dyslipidemia: Nicotinamide is not a good ligand for GPR109A and is not effective in treating lipid abnormalities. Recent clinical trials did not find reduced frequencies of CVD events with nicotinic acid treatment in patients on statins. They did find increased risks for?

serious adverse-effects and new-onset diabetes.

What form of niacin is used in the treatment of Hartnup disease?

Nicotinamide

Lecture 11 Hartnup disease

The RDA for niacin is ? NEs per day for men and women

16 and 14 mg

The term niacin equivalent (NE) is used to quantify niacin intakes and requirements because?

tryptophan may also serve as a precursor for NAD synthesis.

A conversion factor of 60 mg tryptophan to yield?

1 mg niacin is used to calculate the NEs available from tryptophan.

• The RDA is relatively easy to meet with typical intakes of 25-40 mg of NEs per day.

The UL for adults is 35 mg/day but is limited to niacin obtained from?

synthetic sources of nicotinic acid

The UL is based on the dose of nicotinic acid that is associated with?

flushing effects

• The UL is not meant to apply to individuals who are receiving high-dose niacin for the treatment of dyslipidemia under medical supervision.

Biochemical assessment of niacin nutritional status is based on whole blood measures of? and urinary excretion of?

NAD/NADP and urinary excretion of niacin metabolites

Low levels of____ precede pellagra (severe niacin deficiency) and low urinary excretion of ____ indicates mild forms of niacin deficiency

NAD; N-methylnicotinamide

Biotin (Vitamin B7) Biotin was discovered when rats were fed raw eggs as their protein source. Raw egg whites contain? which binds biotin and prevents its absorption

avidin

• Cooking denatures the avidin so it can be acted upon by pancreatic proteases and not interfere with biotin absorption.

Biotin serves as a coenzyme for five?

carboxylase enzymes

Several ____ have been described in biotin-dependent/metabolizing enzymes.

genetic mutations (inborn errors of metabolism)

Biotin is composed of?

two rings and a carbon chain that ends with a carboxyl group.

Biotin is composed of two rings and a carbon chain that ends with a carboxyl group. One of its two rings contains?

sulfur at the number 1 position.

Biotin is released from proteins in food as?

biocytin (biotin + lysine)

Biotin is found in both plant and animal foods. Good sources of biotin include?

1. organ meats

2. egg yolks

3. legumes

4. nuts

5. soy

6. whole grains

7. some fish

Although egg yolks are a concentrated source of biotin, egg whites contain a protein called avidin, which has a high affinity for biotin and thus, decreases its?

availability. Avidin can be inactivated by cooking.

Gut microbes can use what as a precursor of biotin?

cysteine

Biotin is present in foods in what two forms?

“free” and “protein-bound” forms.

Proteinbound biotin is released as what two things via the actions of?

free biotin and biocytin via the actions of pancreatic proteases

Biocytin is hydrolyzed to free biotin and lysine by?

biotinidase

• which is present in pancreatic juice and on the brush border of enterocytes.

Genetic mutations in biotinidase impair the ability to digest?

protein-bound biotin from food (and from that released during the catabolism of biotin-dependent enzymes within the body).

• Biotinidase deficiency can be treated with biotin supplements

Free biotin is absorbed by specific transporters, with?

passive diffusion occurring at high dietary intakes

The uptake of biotin in the intestines occurs via a?

sodium-dependent multivitamin transporter (SMVT).

The uptake of biotin in the intestines occurs via a sodium-dependent multivitamin transporter (SMVT). This transporter is found in what 3 areas?

1. Enterocytes

2. Kidneys

3. Liver

What can impair the function of SMVT and can lead to biotin deficiency?

chronic alcohol

SMVT also co-transports what two things?

vit B3 and lipoic acid

Biotin serves as a coenzyme for five carboxylase enzymes Biotin is transported as free biotin and bound to plasma proteins such as what 3 plasma proteins?

albumin

⍺- and β-globulins

biotin-binding proteins

Biotin is critical to the metabolism of what 3 things?

carbohydrates, fatty acids, and amino acids (leucine).