What is MTHFR C677T SNP and A1298C SNP and what are the ramifications of this?

What is MTHFR C677T SNP and A1298C SNP and what are the ramifications of this?

Hi Charity - thanks for your post and the research showing how to treat these SNPs. You note that supplementing with vitamin B6 as well as B12 and Folate led to lowered homocysteine levels in those with MTHFR SNP. Here is the folate interconversion chart from our book and note that item 5 is where this MTHFR variation is located:

Coenzymes for this reaction include NADP & Vitamin B2 (FAD). I looked for some research and found that indeed Riboflavin supplements assist in lowering Homocysteine in those with MTHFR SNP. Niacin supplementation would seem to work as well although in a brief search I could not find a reference. 

Source:

1/García-Minguillán, et al. Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine. Genes Nutr. 2014 Nov;9(6):435. doi: 10.1007/s12263-014-0435-1. Epub 2014 Oct 17.

2/Methylenetetrahydrofolate Reductase. Austin (TX): Landes Bioscience; 2000-2013. 
https://www.ncbi.nlm.nih.gov/books/NBK6145/.

Homocysteine and B vitamins

High homocysteine levels may be caused by low folate and vitamin B6 levels (1).  B12 levels are also a contributing factor (2). Homocysteine accumulates when it is not converted to methionine in methylation reactions that requires vitamin B12 and folate (2). Additionally, via the Transsulfuration pathway, homocystein will convert to cystathione via vitamin B6 dependant enzymes. (2)

Here is a diagram of this conversion of homocysteine to cysteine (2):

So we see that deficiency in folate, b12 or b6 can lead to elevated Homocysteine levels. Studies have shown that supplementing with these vitamins reduces homocysteine levels. (1,2). 

Sources:

(1) Schnyder G et al. Effect of homocysteine-Lowering Therapy with Folic Acid, Vitamin B12, and Vitamin B6 on Clinical Outcome after PTCA. JAMA 2002; l288:973.

(2) Vitamin B6. Oregon State, Linus Pauling Institute, Miconutrient Center. 

https://lpi.oregonstate.edu/mic/vitamins/vitamin-B6#cardiovascular-disease-prevention (Links to an external site.)Links to an external site.

Vitamin B6 and Dreaming

Vitamin B6 is well known to increase vivid dreaming and causing nightmares (1).  Perhaps there may be a link to the brain glutamate levels and B6. Glutamate is an excitatory neurotransmitter and which may help performance in autistic or ADHD. However over activation at night may be cause of nightmares as well.  There are reports of Chinese Food Syndrome and nightmares among other symptoms all being related to MSG or excessive glutamate. This seems to be an interesting possible early side effect of excessive B6 intake. 

Sources:

1/ Ebben M1, Lequerica A, Spielman A.. Effects of  pyridoxine on dreaming: a preliminary study. Percept Mot Skills. 2002 Feb;94(1):135-40.

Dietary methionine paradoxical effects

Folate's and B12's role in converting Homo cysteine to Methionine. There are several paradoxical issues nutritionists should be aware of. Just a reminder of the reaction we are discussing from our text:

Besides adequate folate and B12 status, wouldn't we think dietary methionine would lower homocysteine? Paradoxically, this is not the case - methionine restriction results in higher homocysteine levels AND increases lifespan in animal models tested! Important to recall that Homocysteine may be the fireman at the fire so to speak in that its elevation may be a marker for a pathological condition not caused by it. 

Source: 

Ables GP et al. Dietary Methionine Restriction in Mice Elicits an Adaptive Cardiovascular Response to Hyperhomocysteinemia
Sci Rep. 2015; 5: 8886.

3 things needed to synthesize CoA

Name and Discuss at least 3 things needed to synthesize CoA.

Coenzyme A (CoA) is needed for oxidation of fatty acids and pyruvate in the TCA. The elements required for CoA synthesis include pantothenic acid, cysteine, and ATP (1,2).

For cells to synthesize CoA, there is a multi-step process (1,2). First vitamin B5 via pantothenic acid kinase enzyme (PANK) is phosphorylated in a rate limiting step to 4'-phosphopantothenate which requires ATP (1,2).

Then Cysteine is added which again requirs ATP (1,2).

The molecule (minus a carboxyl group) moves into the inner mitochondrial membrane where the molecule is adenylated or AMPylated and then phosphorylated to CoA (1,2). Overall 4 ATP molecules are required (1).

Sources:

1/ Leonardi, R., Jackowski, S., 2007. Biosynthesis of Pantothenic Acid and Coenzyme A. EcoSal Plus 2. https://doi.org/10.1128/ecosalplus.3.6.3.4 (Links to an external site.)Links to an external site.

2/ Gropper et al. Advanced Nutrition in Human Metabolism. 7th Ed. Cengage. 2018.

What is Biotin's relationship with Carbohydrate, fat and protein metabolism ( look at coenzymes)?

Interesting how important this vitamin is. For instance, there is evidence of Biotin supplementation improving insulin sensitivity in diabetic mice (1). This makes sense using your list of coenzymes since diabetics are unable to use glucuse, pyruvates gets converted to lactate (causing lactic acidosis if serum glucose rises too high) (similar to deficiency of pyruvate decarboxylase, 2). So instead of making lactate, supplemental Biotin will shunt the Pyruvate to oxaloacetate which takes part not only in gluconeogenesis, but also the citric acid cycle. 

Here is another demonstration of the effect of Biotin supplementation but on human subjects with non-insulin dependent diabetes (3). Noted in this study was that diabetes compared with controls had lower serum Biotin concentrations, and higher serum lactate, pyruvate and fasting blood sugar levels. Oral administration of 9mg a day of Biotin serum glucose, pyruvate and lactate normalized: "These observations suggest that the biotin administration ameliorates abnormal glucose metabolism in diabetic patients, presumably by enhancing the activity of the biotin-dependent enzyme, pyruvate carboxylase, with a subsequent promotion of glucose utilization for the entry into the tricarboxylic acid cycle" (3).

(1) Reddi, A., DeAngelis, B., Frank, O., Lasker, N., Baker, H., 1988. Biotin supplementation improves glucose and insulin tolerances in genetically diabetic KK mice. Life Sci. 42, 1323–1330.

(2) García-Cazorla, A., Rabier, D., Touati, G., Chadefaux-Vekemans, B., Marsac, C., de Lonlay, P., Saudubray, J.-M., 2006. Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann. Neurol. 59, 121–127. https://doi.org/10.1002/ana.20709 (Links to an external site.)Links to an external site.

(3) Maebashi, M., Makino, Y., Furukawa, Y., Ohinata, K., Kimura, S., Sato, T., 1993. Therapeutic Evaluation of the Effect of Biotin on Hyperglycemia in Patients with Non-Insulin Dependent Diabetes Mellitus. Journal of Clinical Biochemistry and Nutrition 14, 211–218. https://doi.org/10.3164/jcbn.14.211 (Links to an external site.)Links to an external site.

Biotin-Responsive Basal Ganglia disease

a) Discuss some signs and symptoms of biotin deficiency. b) Are the certain drugs that can deplete this vitamin?

Case report you posted of acute quadriplegia in an 10 year old that had presumed Biotin deficiency and found to have basal ganglia lesions. I found an analysis of 10 patients with Biotin-Responsive Basal Ganglia disease in a 2012 report if anyone wants more info (1). Although basal ganglia is grey matter, there are reports of Biotin supplementation positively impacting Multiple Sclerosis, primarily a white matter disease (2). So one of the signs of Biotin deficiency seem to include neuro-inflammatory effects. 

1/Tabarki, B., Al-Shafi, S., Al-Shahwan, S., Azmat, Z., Al-Hashem, A., Al-Adwani, N., Biary, N., Al-Zawahmah, M., Khan, S., Zuccoli, G., 2013. Biotin-responsive basal ganglia disease revisited: Clinical, radiologic, and genetic findings. Neurology 80, 261–267. https://doi.org/10.1212/WNL.0b013e31827deb4c (Links to an external site.)Links to an external site.

2/Sedel, F., Papeix, C., Bellanger, A., Touitou, V., Lebrun-Frenay, C., Galanaud, D., Gout, O., Lyon-Caen, O., Tourbah, A., 2015. High doses of biotin in chronic progressive multiple sclerosis: A pilot study. Multiple Sclerosis and Related Disorders 4, 159–169. https://doi.org/10.1016/j.msard.2015.01.005 (Links to an external site.)Links to an external site.

Describe the 3 types of Beriberi

1. Describe the 3 types of Beriberi.
2. Explain the relationship between B1 and membrane and nerve conduction?

Beriberi is a chronic condition of thiamine deficiency, for which there are 2 main types: Wet Beriberi and Dry Beriberi. The Wet form is so names are it affects the cardiovascular system and causes swelling of legs along with shortness of breath and tachycardia. The Dry form impacts the nervous system and causes a neuropathy due to damage of the peripheral nerves. A lesser known 3rd form is Acute beriberi seen mostly in infants and results in cardiomegaly, arrhythmia, lactic acidosis, and failure to thrive. (1)

Major clinical signs of beriberi include (3):

• Hyporeflexia
• Hypesthesia (a diminished capacity for physical sensation, especially of the skin.)
• Edema
• Lowered diastolic blood pressure
• Tenderness of calf muscles when grasped

Thiamine “is an incredibly active molecule” and play prominent roles in many aspects of cellular metabolism which is vital to many forms of life (3). One key factor is thiamine’s pyrophosphate ester, thiamine diphosphate (TPP) which is a cofactor for enzymatic reactions that cleave alpha-keto acids:

“TTP activates decarboxylation of pyruvate in the pyruvate dehydrogenase complex. This complex is a group of enzymes and cofactors that form acetyl CoA that condenses with oxaloacetate to form citrate, the first component of the citric acid cycle. Since pyruvate is derived from glucose via the Embden–Meyerhof pathway, it should be emphasized that the energy drive from oxidation of glucose is highly dependent upon TPP. It is also a cofactor in the decarboxylating component of alpha-ketoglutarate dehydrogenase, an important link in the citric acid cycle.”

One key point is that a diet high in simple carbohydrates (glucose) “automatically” requires an increased need for thiamine! (3). Therefore, it follows that a modern diet high in “sugar” but low in nutrient dense foods may cause berierbi symptoms. In this article "It is very likely that many of the poorly understood symptomatology seen today that responds to nutrient therapy is caused by a mixture of marginal classic nutritional diseases, including beriberi, pellagra and scurvy. In our experience it is certainly true that symptoms arising from autonomic dysfunction are usually reversible by nutritional therapy." (3)

As far as the nerves and membranes: thiamine is important for the nerve action potential allowing for proper conductance of nerve signals, especially at the synapse where it is also involved in production of acetylcholine (the neurotransmitter that mediates nerve transmission across the synapse) (2). Also, thiamine appears to be involved in nerve tissue repair (2).

Sources:

1/ Hammond, N., Wang, Y., Dimachkie, M.M., Barohn, R.J., 2013. Nutritional Neuropathies. Neurologic Clinics 31, 477–489. https://doi.org/10.1016/j.ncl.2013.02.002 (Links to an external site.)Links to an external site.

2/ Manzetti, S., Zhang, J., van der Spoel, D., 2014. Thiamin Function, Metabolism, Uptake, and Transport. Biochemistry 53, 821–835. https://doi.org/10.1021/bi401618y (Links to an external site.)Links to an external site.

3/ Lonsdale, D., 2006. A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid Based Complement Alternat Med 3, 49–59. https://doi.org/10.1093/ecam/nek009 (Links to an external site.)Links to an external site.

Edited by Mason Gasper on Dec 5 at 6:07pm

Nutrient poor high carbohydrate diets, can lead to symptoms of beriberi

Nutrient poor high carbohydrate diets, can lead to symptoms of beriberi, and that thiamine deficiency can occur even when supplements are given. I'm sure there are other articles that are good, but I have found thiamine hard to understand because the mechanisms it uses are so varied. Here is the one I found very helpful:

Lonsdale, D., 2006. A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid Based Complement Alternat Med 3, 49–59. https://doi.org/10.1093/ecam/nek009 (Links to an external site.)Links to an external site.

In this article the author reports: "Necropsy studies have suggested that TD is underdiagnosed in life because the classical clinical presentations are either uncommon or unrecognized. Marginal TD [thiamine deficiency] was found in 31% and definite deficiency in 17% of 36 non-demented, community-dwelling patients admitted to an acute geriatric unit. There is no doubt that severe TD is lethal but marginal deficiency can give rise to symptoms that are commonly mistaken for functional disease. A very early experiment in human subjects showed that marginal deficiency produced a multitude of symptoms that might, under ordinary clinical conditions, be regarded as functional in nature. The symptoms disappeared quickly when a thiamine sufficient diet was restored."

Interesting to consider MARGINAL thiamine deficiency and then looking for it in our patients. 

4 D's of Pellegra and physiology of how they happen?

"modern maladaptations" (1) related to Pellagra. I would like to a summary of an article which is an interesting theory to consider at the very least. NAD+ is an important part of energy metabolism and its reduction to NADH for dehydrogenase reactions in the mitochondria seems to require a constant supply of NAD+ by diet or by gut microbes (1). One major dietary source of NAD+ (via nicotinic acid) is meat (1). As you point out when meat availability is low, Pellegra may result (1).

I'll see if I can summarize this paper, but it has some interesting epidemiological graphs that I'd like to present to you. First, the argument goes that there does appear to be a symbiotic relationship that is theorized to have developed during "feast or famine" days of hunter gatherer period of human evolution (1). As such, when meat is scarce and fiber type foods are eaten in its place, the gut microbes will use the starch eaten to produce NAD+ (1). In days of feast and famine, the symbiosis worked well. But as meat ingestion has steadily become a staple in the diet of the affluent, and high fiber starchy food a staple in the non-affluent we get a divergence of effects. In the nonmeat eaters, you can see Pellegra. In the meat eaters, you are seeing modern illness in the form of immune reactions and dysbiosis as a stronger immune response is mounted against gut bacteria (all from 1). 

Here are some of the interesting graphs from the article (I hope I adequately explained the steps in the thinking to get to these graphs):

First it is of interest that TB rates went down as meat ingestion goes up... (pre-medical rx):

So, stronger immune reactions against the gut microbes help with infection, but in its place with more consistent meat ingestion we have modern disease (I'm just showing the correlation, not causation of course) of cancer and diabetes, as well as allergies:

Interesting here the difference between areas of possible Niacin excess versus deficiency and the resulting conditions (as per source 2):

So, the article argues that niacin toxicity is associated with a group of conditions that are modern:

And recommends that you tread the middle ground with niacin supplements:

Sorry if not clear, I left many gaps and its clear this is a working hypothesis, but I found it an interesting way to work through some topics with Niacine. The article can be found online here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419340/ (Links to an external site.)Links to an external site.

Source: Lisa J Hill and Adrian C Williams. Meat Intake and the Dose of Vitamin B3 – Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures? Int J Tryptophan Res. 2017; 10: 1178646917704662.

What neurotransmitters are dependent on Vitamin C?

What neurotransmitters are dependent on Vitamin C?

Among Vitamin C’s many functions, one of its most important tissues it serves may be the brain as the CNS contains the highest concentrations of ascorbate in the body (1).

In the Central Nervous System, vitamin C performs its well-known antioxidant role, but also as a cofactor in enzyme reaction including the synthesis of neurotransmitters, norepinephrine and serotonin (1).  Ascorbate serves as a cofactor for dopamine B-hydroxylase in coverting dopamine to norephinephrine (1).

Studies show that vitamin C is regionally distributed in the brain and provides additional evidence that neurotransmitters rely on Ascobate funciton (1). Vitamin C contained in the forebrain in high levels may be associated with the high levels of catacholamine (norepinephrine) function in this area (1). Other areas of research suggest vitamin C role in dopamine and glutamate neurotransmission as a neuromodulator with possible mechanisms related to protection against excitotoxicity of NMDA receptor activation (1).

Other reports suggest that ascorbate plays a role as a cofactor for tryptophan-5-hydroxylase  in tryptophan conversion to 5-hydroxytryptophan in serotonin production (2).  In patient's deprived of ctamin C, states of sadness, reduced cogntitive abilities, and fatigue emerge (2). Reduced levels of both serotonin and norepninephrine have been show to be related to depressed mood (2).

Based on these reports, vitamin C has a significant impact on several neurotransmitters and may play an important role in mental health.

Sources:

1/Harrison, F.E., May, J.M., 2009. Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free Radical Biology and Medicine 46, 719–730.  ttps://doi.org/10.1016/j.freeradbiomed.2008.12.018

2/ Prerana Gupta, Sanchit Tiwari, Jigar Haria. "Relationship Between Depression and Vitamin C Status: A Study on Rural Patients From Western Uttar Pradesh in India". International Journal of Scientific Study. 2014;1(4):37-39.

Vitamin C and NO

Vitamin C stimulating the production of NO is interesting:

"The NO theory of aging suggests that repeated infections create progressive oxidative damage leading to coronary disease and neurodegenerative conditions (1,2). The principal mechanism tested is when bacterial lipopolysaccharides (LPS) injected, NO Synthetase is induced (via an IL-1) mediator within 2-4 hours (2). The blood brain barrier does not appear to keep LPS out of the central nervous system (3), and an intense NO response is seen in the brain (1,2). The effect of NO is to inactivate enzymes which leads to cell death of invading virus as well as host cells (1). Antioxidant vitamin C and E appear to be beneficial in attenuating the NO oxidant effect (1,2). "

So interesting that vitamin C may regulate NO function in that it stimulates NO production but also attenuates NO effect. 

Sources:

1/ McCann S et al. The nitric oxide theory of aging revisited. Ann N Y Acad Sci. 2005 Dec;1057:64-84.

2/McCann S et al. The nitric oxide hypothesis of aging. Exp Gerontol. 1998 Nov-Dec;33(7-8):813-26.

3/Wei-Ye L et al. Increasing the Permeability of the Blood–brain Barrier in Three Different Models in vivo. CNS Neuroscience & Therapeutics. 21 (2015) 568-574.

Vitamin C and Smoking

What does smoking do to Vitamin C? Now make the connections to smokers and strokes and heart attacks. 

In the standard model that elevated cholesterol leads to atherosclerosis (and heart attacks and stroke), then vitamin C certainly has a beneficial impact as 500 mg/d of vitamin C daily can result in a significant decrease in serum LDL cholesterol and triglyceride concentrations (1). Smoker preferences for reduced citrus intake in addition to smoking itself causing reduced seurm Vitamin C creates a risk of severe Hypovitaminosis for C vitamin (2). In turns, vitamin C effect on LDL levels is associated with higher atheroslcerotic risks. 

Sources:

(1) McRae, M.P., 2008. Vitamin C supplementation lowers serum low-density lipoprotein cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials. J Chiropr Med 7, 48–58. https://doi.org/10.1016/j.jcme.2008.01.002 (Links to an external site.)Links to an external site.

(2) Schectman, G., Byrd, J.C., Gruchow, H.W., 1989. The influence of smoking on vitamin C status in adults. Am J Public Health 79, 158–162.

B Vitamins Summary

B1 / Thiamine
B2 / Roboflavin
B3 / Niacin
B4
B5/ Pantothoic acid
B6 /
B7 / Biotin

B1 + B2 + B3 ENERGY
- don't take at night

B6 has diuretic effect, don't take at night

Biotin Review

BIOTIN

Egg white injury - eating raw eggs results in hair loss, dermatitis, neuromuscular problems.

Structure:

• Ureido ring
• Thiophene ring
• Valeric acid side chain

SOURCES

Made by bacteria in colon
Major food: liver (21 ug), milk, soy, egg yolk (4ug)

Found free or bound to protein
Egg whites have biotin bound to Avindin which does not release

DIGESTION, ABSORPTION, METABOLISM, and EXCRETION

Protein bound biotin requires pepsin yields free biotin or BIOCYTIN
BIOCYTIN is biotin bound to Lysine, required BIOTINIDASE hydrolysis
Biotinidase Deficiency = inborn error of metabolism

Absorbed passively or by carrier mediation via SHARED MULTIVITAMIN TRANSPORTER (SMVT)
ETOH impairs absorption

In plasma, 80% free biotin, [ ] 200-750 ug/mL
Stored in muscle, liver, brain

FUNCTION/MOA

Coenzyme carrier for transfer of activated bicarbonate to substrates for:

• Fatty acid synthesis
• Gluconeogenesis
• Metabolism of branched chain amino acids
• Role in ELONGASE enzymes that convert the O-6 Linolenic Acid and O-3 A-Linoleic Acid into longer chain fatty acids such as DHA and EPA from ALA

Uses

Blood glucose mgt - improves fasting blood glucose
Ratio of LDL to HDL and TG:HDL
Convert o-3 and o-6 to arachadonic acid and EPA and DHA
Vegetarians should supplement to allow for these long chain PUFA
Hair skin nail problems

RDA

AI 30 ug / d

DEFICIENCY

rare ~ raw eggs

• Neurological - parestesias, ataxia, seizures
• Cutaneous

Risk: GI disorders, Illness with increased need for biotin, medications that interfere with absorption (sulfa, anticonvulsants, antibiotics).

TOXICITY

no TUL

Assessment:

Serum <200 ug/Ml

Urine

Pantothenic Acid Review

PANTOTHENIC ACID

Structure

• B-alanine
• pantoic acid
• joined by amide linkage

SOURCES

Found everywhere! Deficiency is rare

DIGESTION, ABSORPTION, METABOLISM, and EXCRETION

FUNCTION/MOA

RAW MATERIAL for CoA - without Pantathenic Acid we would have no:

• Acetyl CoA
• Malonyl CoA
• Fatty Acyl CoA
• Hydroxy 3 Medroxyl Glutyl CoA (HMG-CoA)

Example is the cholesterol pathway synthesis - so CoA vital for cholesterol:

Fxn bind carboxylic acid and transfer them to other molecules

Uses:
Chronic fatigue
Anemia related fatigue

Niacin B3 Review

NIACIN B3

Generic term for NICOTONIC ACID AND NICOTINAMIDE (NIACIN-AMIDE)

• Nicotinamide Nucleotides:
• Nicotinamide Adenine Dinucleotide (NAD)
• Nicotinamide Adenine Dinucleotide Phosphate (NADP)

SOURCES

Primarily from fish and meats (especially beef tongue 15 mg / 3 oz)

In coffee and tea

Bacteria produce niacin

Supplement and fortification are NICOTINAMIDE

In animal food:

• NICOTINAMIDE
• Nicotinamide Nucleotides in OXIDIZED FORM:
• Nicotinamide Adenine Dinucleotide (NAD+)
• Nicotinamide Adenine Dinucleotide Phosphate (NADP+)

In Plant food: NICOTINIC ACID

When bound to complex carbohydrates, called NIACYTIN

When bound to small peptides: NIACINOGENSE

Lime water will help release bound forms of niacin.

TRYPTOPHAN can be used by liver to produce NIACIN (3% of body stores)

• Hartnup disease (genetic inability to transport tryptophan during absorption)

DIGESTION, ABSORPTION, METABOLISM, and EXCRETION

FUNCTION/MOA

Over 200 enzymes - primarily dehydrogenases - require NAD or NADP which acts as a hydrogen donor or electron acceptor

COENZYME ROLES IN NUTRIENT METABOLISM AND ENERGY PRODUCTION

• NADH - reduced form of NAD
• Transfer electrons in the ETC
• NADPH
• acts as a reducing agent in many pathways:
• fatty acids
• cholesterol
• steroid
• Oxidative reactions in which no acute changes. reduced to NADH
• Glycolysis
• Oxidative decarbosylation of pyruvate to acetyl-coA
• oxidation of acetyl coa in the TCA cycle
• B oxidation of fatty acids
• Oxidation of ethanol
• Aldehyde dehydrogenase catabolizes B6 to excretory product, requires NAD
• NADP reduced to NADPH
• Pentose phophate pathway
• Malate aspartate shuttel
• Nutrient metabolism (see above)

NONREDOX ROLES
ADP transferred to acceptor molecules, typically involving cellular processes like DNA repair, chromatin structure, intraceullular calcium signallying.

USES

• 6g/d Nicotinic Acid
• Hyperlipidemias
• Flushing
• Liver injury
• Gout
• Niacinamide does not lower cholesterol
• reduces skin inflammation
• 3g/d can cause headache, GI distress, impaired glucose tolerance, liver damage

RDA:

60mg tryptophan = 1 mg niacin

Niacin equivalents - 16 mg and 14 mg

DEFICIENCY

Pellegra

• Dernatitis, Dementia, Diarrhea, Death
• Neurological manifestations
• GI manifestations

Risks: Malabsorptive, INH, Mercaptopurine, etoh, HIV, cancer

TOXICITY

Related to vasodilatory effects

35 mg a day

ASSESSMENT

Urine excretion

Serum or RBC: NAD:NADP ratio ~ 1.0

Riboflavin B2 Review

RIBOFLAVIN (B2)

Structure:

• Flavin - yellow colored, seen in urine
• Ribitol

Coenzymes:

• FMN
• FAD

SOURCES

DIGESTION, ABSORPTION, METABOLISM, and EXCRETION

FUNCTION/MOA

2 coenzyme forms of Riboflavin - FAD FMN

• Flavoproteins exhibit a wide range of redox potentials so can play a variety of roles in intermediary metabolism
• FAD and FMN have ability to accept a pair of hydrogen atoms
• Reduction of FAD and FMN results in FADH2 and FMNH2

Role in Nutrition and Energy Production

• Electron transport chain
• B6 metabolism
• Pyridoxine phosphate oxidase (converts PMP and PNP to PLP, dependant on FMN)
• L-amino oxidase uses FMN in the dehydrogenase of L-amino acids to imino acids
• Oxidative decarboxylation of pyruvate and a-ketoglutarate
• Succinate dehydrogenase removes electrons from succinic acid to form fumarate
• Fatty acid beta-oxidation, acyl-coA dehydrogenase requires FAD
• Sphingonine oxidase, requires FADA
• Coenzyme for an oxidase such as Xanthine Oxidase involved in purine metabolism
• Aldehyde oxidate
• Synthesis of folate
• Synthesis of niacin from tryptophan
• Choline metabolism
• Monoamine oxidate (dopamine)
• Glutathione reductase 
• Eral and sulfhydryl oxidases, impair folding with B2 deficiency
• THioredoxin reductase
• Ribonucleotide reductase
• Hydrogen peroxide production from O2

USES

• Migraine headaches 400 mg
• Glutaric acid type 1
• Beta-oxidation of fatty acids in mitochondria

RDA

1.3 mg/d and 1.1 mg/d

Deficiency

Ariboflavinosis

• 3-4 months of inadequate intake
• cheliosis, angular stomatitis, glossitis
• skin becomes reddened scaly greasy painful
• conjuctivitis
• neuropathy
• RXb5-30mg daily

At risk: etoh, hypothyroidism, adrenal insufficiency, DM, trauma, stress, TCAs

Toxicity

no TUL

Assessment

Measurement of activity of FAD-dependent enzyme erythrocyte glutathione reductase

• Activity Coefficients
• AC 1.2 to 1.4 normal
• AC>1.4 riboflavin deficiency

FAD-dependent enzyme pyridoxamine phosphate oxidase

Urinary riboflavin excretion with <25 ug/g creatinine = deficiency

Thiamine Review

THIAMINE - VITAMIN B1

Structure:

• Pyrimidine ring
• Thiazole moiety
• Sulfur bridge

SOURCES:

DIGESTION, ABSORPTION, METABOLISM, and EXCRETION

Phosphorylated forms must be digested

Absorption is efficient

• Inhibited by etoh
• Antithiamin factors occur in raw fish, coffee, tea
• Vitamin C prevents thiamine destruction

Re-phosphorylation occurs in gut or liver cells

Blood cells take up and phosphorylate circulating B1

Retention in tissues is limited

• 1/2 life is less than 3 weeks

Excreted in urine

FUNCTION/MOA

Thiamine has ESSENTIAL COENZYME and NON-COENZYME ROLES

• Energy production and nutrient metabolism
• Coenzyme roles in pyruvate dehydrogenase
• a-keogluterate deyhyrogenase
• Branched chain a-keto-acid dehydrogenase complexes
• Nutrient metabolism
• Inter conversion of phosphoylated sugars for the syntheses of nucleotides and some B-vitamin coenzymes (like transketolase)
• Nervous system functions (nonconenzyme)

CO-ENZYME ROLES

Energy Production and Nutrient Metabolism

• Energy transformation (coenzyme role)
• Pyruvate dehydrogenase complex
• 3 enzymes make up this complex
• 4 vitamins are needed: TDP, FAD, NAD, CoA
• Also: ATP and magnesium
• Alpha-ketoglutarate dehydrogenase complex
• Branched chain alpha-ketoacid dehydrogenase complex
• Failure to oxidize ~ Maple Syrup Urine Disease
• LIV if you hang from a BRANCH
  Leucine Isoleucine Valine are Branched Chain Amino Acids

• Reductions or inhibitions 
• Diminished synthesis of ATP
• Impaired synthesis of Ach
• Impaired synthesis of fatty acids, cholesterol
• Accumulation of:
• Pyruvate
• Lactate
• a-ketogluterate

Nutrient Metabolism - Interconversion of Phosphorylated Sugars

• TDP also functions as Transketolase, a key enzyme in the Pentose phosphate pathway for pentose and NADPH production.

• 5- Carbon Sugars: ribose

NON-CO-ENZYME ROLES: NERVOUS SYSTEM FUNCTIONS

Role in regulating Sodium Channels

Production of Ach

Membrane and nerve conduction (non-coenzyme role)

TREATMENT ROLES: MSUD: 100mg+

METABOLISM AND EXCRETION

Urinary excretion

RDA

1.2 mg per day men 1.1 mg women

DEFICIENCY

Deficiency impacts energy production

Few weeks to months of inadequate diet

Initial: fatigue, nausea

Dry Beri Beri - neuropathy, muscle weakness, cramping

Wet Beri Beri - cardiomegaly, tachycardia, edema

Acute Beri Beri - nausea vomiting lactic acidosis

RX: 30 mg TID mild, 100-800 mg daily

Risk: etoh, older, malabsorption

TOXICITY

No TUL

ASSESSMENT

Thiamine and/or TDP in blood or urine

Erythrocyte tranketolase activity in hemolyzed whole blood