Nut Vitamins (6/7)

• an essential nutrient in humans
• 1. it's an electron donor (antioxidant) in a number of reactions
• 2. it contributes to protein & neurotransmitter metabolism
• 3. facilitates absorption of non-heme iron in the small intestine
• active form: L-ascorbic acid
• most stable form: dehydroascorbic acid (DHAA)
• excreted as: diketogulonic acid (irreversible)

• Collagen synthesis: hydroxylation of proline (for triple helix) & lysine (for hydroxylysine cross-links)
• Carnitine synthesis: made from lysine & methionine w/ vitamin C as cofactor (among other things)
• Neurotransmitter metabolism: C is used in tyrosine catabolism & hydroxylation of dopamine --> norepineph.
• Antioxidant function: in PMN, monocytes, macrophages, lung and eye, & in the regeneration of reduced vitamin E

Hydroxylases; ascorbic acid (Vitamin C is the co-factor)

• it's easily destroyed by oxidation, heat, exposure to air, an alkaline medium, & by contact with copper & iron, which oxidize it to dehydroascorbic acid (DHAA)
• this explains in part why the Vitamin C content of foods is subject to degradation with storage & cooking
• it's labile & content will diminishes with storage, long shelf time, & cooking

FROZEN vegetables usually have more Vitamin C that their canned or fresh counterparts because it's preserved in the frozen state

• it's widely found in any plant that is fresh & rapidly growing (eg. fruits, some vegetables, while dormant foods such as nuts, seeds and grains are poor sources)
• synthesized by some non-primates and most plants from glucose & fructose

• 1. organic acids
• 2. antioxidants

• in the small intestine by specific transporters
• plasma concentrations are tightly controlled, mediated by absorption but more so by RENAL handling: ascorbic acid is filtered by the glomerulus & reabsorbed in the proximal convoluted tubule

• low doses, normal concentrations: nearly 100% is reabsorbed
• high doses: less than 50% is reabsorbed

• in humans ascorbic acid is catabolized to oxalic acid
• there is a risk for oxalate kidney stones in susceptible persons who consume a large amount of vitamin C (aka it may potentiate oxalate nephrolithiasis)

• scurvy
• weakness and lassitude
• skin and soft tissue (impaired wound healing, petechial hemorrhage, perifollicular hyperkeratosis, ecchymosis)
• oral issues: swollen gums that bleed easily & are friable, tooth loss
• coiled hair
• joint issues: bleeding into joints, arthralgias
• cardiopulmonary issues: shortness of breath, pericardial bleeding
• bone: impaired growth & bowing, subperiosteal hemorrhage, impaired healing
• CNS issues (depression, confusion, hysteria, hypochondriasis)
• infection
• internal bleeding

• intake adequate to maintain normal neutrophil concentrations & urinary excretion
• women: 75 mg/day
• men: 90 mg/day

• 35 mg/day higher than for nonsmokers
• this is because smoking leads to oxidative stress and smokers generally have reduced circulating concentrations of ascorbic acid

• cigarette smoke oxidizes a methionine residue on alpha1-antitrypsin involved in binding elastase
• methionine --> methionine sulfoxide
• Oxidation of this residue PREVENTS inhibition of elastase, results in over-degradation of lung elastin fibers --> lung scarring & emphysema
• b/c Vitamin C can act as an antioxidant (probably due to it's OH group) reducing harmful free radicals, it can help mitigate the effects of smoking

• 2 g/day
• it's based on the gastrointestinal side effects of diarrhea and bloating
• also excess intake can lead to increased urinary excretion of oxalate & uric acid (hyperoxaluria), both of which may potentiate kidney stones in predisposed individuals
• + enhanced iron absorption

• a cofactor for enzymes such as transketolases & dehydrogenases & is essential in energy utilization and synthesis
• in nerves, thiamine participates in synthesis of acetylcholine, glutamate, + GABA, & is released from nerves with nerve stimulation
• it's found in whole grains, some vegetables, legumes, & pork, but less so in beef, lamb, poultry, or dairy

functions in the pentose phosphate pathway to produce NADPH for biosynthesis

• such as pyruvate dehydrogenase, which converts pyruvate to acetyl CoA
• a thiamine deficiency causes E1 to not function properly, meaning pyruvate can only be converted to lactate

• 1. the processing of grains: which is why it's added to enriched grains and cereals
• 2. thiaminases: found in fish, shellfish, ferns, & some microorganisms
• 3. antithiamine compounds

• compounds that degrade thiamine in raw food or in the digestive system (after consumption of foods that have thiamine)
• found in fish, shellfish, ferns, & microrganisms
• are thermoLABILE, aka destroyed by cooking (heat)

• cleaves thiamine to form oxidized inactive comounds
• *is thermoSTABLE
• found in coffee, teas, betel nuts, & other foods w/ polyphenol-like compounds

nope

• absorption occurs most in the jejunum & ileum
• once inside intestinal cells, thiamine is trapped there by phosphorylation
• it's secreted into the portal circulation through SLC19 transporters or by basolateral export to circulate free form or as thiamine monophosphate
• thiamine phosphates are sequestered in RBCs & other tissues

• muscle
• there is also some stored in the liver

• in several tissues, including intestines and kidney
• mutations for these carriers cause thiamine deficiency (DISEASE) due to impaired transport

• 30 mg
• roughly equal to 30 days of intake at the RDA
• the rapid turnover of thiamine requires near CONTINUOUS intake to prevent deficiency
• there is renal excretion of thiamine and metabolites

• alcohol abuse
• ethanol prevents basolateral absorption of thiamine from the small intestine endothelium, which manifests as thiamine deficiency
• it also impairs it's phosphorylation to the active cofactor diphosphate form (TPP, thiamine pyrophosphate)
• there are reduced liver stores of it due to liver fibrosis/cirrhosis

• Poor dietary intake
• Alcoholism
• Persistent vomiting (especially after bariatric surgery, hyperemesis gravidarum)
• Gastrointestinal disease
• HIV/AIDS
• Refeeding syndrome
• A limited diet that contains large amounts of foods w/ thiaminases or antithiamines (raw fish, coffee)

• cellular energy failure
• manifests as fatigue, central + peripheral nervous system defects, & cardiovascular issues
• lactate accumulation
• fewer TCA intermediates
• less high energy phosphate synthesis
• less NT synthesis

• Peripheral neuropathy, distal > proximal
• Involves motor and sensory nerves
• Diminished reflexes
• Calf tenderness

• Tachycardia & low peripheral resistance
• Edema
• Cardiomegaly & high output congestive heart failure
• Peripheral neuropathy

• characterized by cardiac & CNS manifestations
• it can occur in mothers who are thiamine deficient but asymptomatic, which may lead to delays in the diagnosis in the infant

• can arise from deficiency of vitamin B1 (thiamine) - acute/early
• C confusion
• O ophthalmoplegia
• A ataxia (difficulty with motor control)
• T thiamine Tx

• can arise from deficiency of vitamin B1 (thiamine) - chronic/late
• R retrograde amnesia
• A anterograde amnesia
• C confabulation (tall tales)
• K Korsakoff's psychosis

• by depletion/repletion studies & erythrocyte transketolase activity
• is such an assay, thiamine is added to red blood cells and the increased activity of transketolase is measured
• a deficiency is associated with greater degrees of transketolase activity stimulation by addition of thiamine

THERE IS NON3! CAN NEVER HAVE TOO MUCH!

• also known as nicotinic acid/nicotinamide/niacinamide
• forms the coenzymes NAD (nicotinamide adenine dinucleotide) & NADPH (nicotinamide adenine dinucleotide phosphate)

• tryptophan
• however, niacin/NAD deficiency can still occur when tryptophan is sufficiently present in the diet to synthesize NAD

meats, fish, yeast, some nuts, whole grains, & wheat germ

• it may be bound to carbohydrates
• unless it's treated with alkali (eg. limewater as used for corn tortillas), this form of niacin is NOT bioavailable
• limewater is the common name for an saturated solution of calcium hydroxide

• dyslipidemia
• niacin (not nicotinamide though) binds to & stimulates a G-protein-coupled receptor, which initiates a cascade that inhibits fat breakdown in adipose tissue -> LESS VLDL & LDL in blood

• as nicotinamide
• approximately 1/3 of plasma nicotinamide is bound to plasma proteins

• as coenzymes NAD & NADPH
• excess hepatic NAD may be stored in small amounts unbound to proteins

coenzymes involved in energy utilization and synthetic reactions in processes such as glycolysis, the TCA cycle, beta-oxidation of fatty acids, ethanol oxidation, ADP-ribosylation, DNA excision repair, cell replication, cell differentiation, & apoptosis

• to donate its electrons to the electron transport chain allowing the generation of ATP
• NADPH is a reducing agent in multiple biosynthetic reactions

• those of lower socioeconomic class who primarily consume corn, which contains niacin but it remains complexed to carbohydrate & is unavailable unless treated with alkali
• people who have diets characterized by 3 Ms:
• 1. Maize (if untreated w/ alkali)
• 2. Meat (if poor quality + high fat)
• 3. Molasses

because sorghum diets have a high leucine content, which interferes with conversion of tryptophan to NAD

• defective tryptophan transporter; leads to abnormal secretion of AAs (including tryptophan and those like it which use the same transporter) in the urine
• it's characterized by dermatitis, diarrhea, & dementia (3 Ds) similar to pellagra b/c tryptophan is a precursor of niacin --> nicotinamide --> NAD+ coenzyme, but Hartnup's is less severe & more intermittent
• it's effects are seen mostly in brain & skin

• the array of symptoms that occur secondary to carcinoid TUMORS, including flushing, diarrhea, heart failure, or bronchoconstriction
• can CAUSE niacin deficiency in that the tumor overuses tryptophan to endogenously synthesize serotonin & kallikrein (+ inflammation stuff)

• caused by niacin deficiency, characterized by the four Ds:
• 1. Dermatitis: in sun-exposed areas of the skin; skin of pellagrins is lower in urocanic acid (degradation product of histidine), which contributes to UV light absorption
• 2. Diarrhea: due to mucosal atrophy + inflammation in GI tract
• 3. Dementia: + mood disorders, altered mental status, neuropathy, or muscle weakness
• 4. Death

• males: 16 mg NE/day
• females: 14 mg NE/day
• niacin intake is expressed in niacin equivalents (NE), meaning intake can be of niacin or of tryptophan (60 mg tryptophan are needed to synthesize 1 mg of niacin)

• 35 mg/day, which is based on flushing
• high doses of nicotinic acid or nicotinamide can result in:
• GI symptoms (heartburn, nausea, vomiting), Hepatotoxicity, Hyperuricemia, Gout (niacin competes with uric acid for excretion), Decreased insulin sensitivity, & Glucose intolerance

• important for nucleotide & methionine (AA) synthesis, as well as methylation
• made up of a pterin ring connected to glutamic acid residue via a para-amino benzoic acid bridge (lol)

• folates are found in food
• folic acid is the synthetic form of folate found in fortified food supplements (stable oxidized form of folate with one glutamic acid)

• it's widely distributed in food, especially food fortified w/ folate
• good examples = spinach, liver, lima & kidney beans, brussel sprouts, broccoli, & yeast

it prevents neural tube defects, spina bifida and anencephaly

• in the SI mucosa
• folate is made available after food has been digested, it's been released from some matrix, & converted to a form we can use
• it is stored in liver, resulting in small daily losses when bile is secreted
• however the liver store can last a person for ~2-3 months
• b/c folate is H2O soluble we don't store too much & resupply should be frequent

• 10-20 mg: 4-15 mg stored in liver
• daily folate losses are 200 mcg, 1-2% of stores
• periods of increased folate demand (pregnancy & lactation) may result in more rapid utilization of folate stores

• by the concentration in plasma or in RBCs
• plasma folate reflects recent intake
• RBC folate remains relatively stable over the lifespan of the cell, thus decreased RBC folate suggests a more chronic deficiency
• RBCs eventually become macrocytic due to folate deficiency
• anemia due to ineffective hematopoesis occurs later in deficiency
• can also check liver stores

• FOLIC ACID is better absorbed; over 85% is absorbed from a given dosage
• compared to 60% of folate in a food containing it
• bioavailability of folate from food is good, but not as good as for the synthetic acid
• (naturally-occurring folates in food: ~60%
• absorption of folic acid in supplements: approaches 100%
• absorption of folic acid in fortified foods: > 85%)

• in the reaction catalyzed by methionine synthase, both B12 & methyl THF act as 'coenzymes'
• the B12 is the molecule that actually holds & transfers a methyl group (methylcobalamin) onto homocysteine, forming methionine
• if there is a deficiency of either B12 or folate, this reaction can't happen & homocysteine may accumulate

• heart disease
• (homocystinurea - but that's usually because of a defective enzyme)

• in addition to just not having enough folate, a deficiency in Vitamin B12 (cobalamin) causes a folate deficiency, because without it the CH3 group in methyl tetrahydrofolate cannot be transferred
• folate is sequestered in its non-physiologic form
• sequestering of CH3 in methyl THF results in the same side effects as a folate deficiency

• a duel effect
• inadequate folate intake predisposes people to colorectal or breast cancer
• overly high levels of folate can precipitate/cause (colorectal) cancer, as it accelerates the growth of cancer or precancerous cells

• 1. someone with a poor diet
• 2. alcoholics (ethanol inhibits absorption of folate, similar to thiamine)
• 3. those who suffer from generalized malabsorption (eg. caused by illness)
• 4. certain medications (eg. anticonvulsants)

• the first cells/tissue to be affected = those that rapidly divide, aka the GI tract & bone marrow
• in the bone marrow megaloblastic anemia may be seen
• diarrhea & malabsorption are seen as a result of the GI tract being affected

• anemia caused by inhibition of DNA synthesis during RBC production
• When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage
• this leads to continuing cell growth without division, which presents as macrocytosis, large cells w/ a ton of cytoplasm but a slow growing nucleus
• hypersegmented neutrophils & mishaped RBCs are characteristic of this disease
• 

• functions as a cofactor for 2 enzymes, methionine synthase in the the cytosol (homocysteine -> methionine) & methylmalonyl CoA in the mitochondria (methylmalonyl CoA -> succinyl CoA
• a water soluble family of vitamins

• methyl cobalamin
• 5-deoxyadenosylcobalamin

• meat, poulty, fish, dairy, eggs
• fortified foods
• yeast & some fermented foods
• *vegans tend to be deficient

• in food B12 is protein bound - must be separated in order for absorption to occur; this is done via 2 mechanisms in the stomach
• 1. gastric acid
• 2. protease enzymes (eg. pepsin)
• *if either is missing, defective, or perhaps affected by medication, B12 absorption is compromised

• R-binders, a glycoprotein found in gastric juices & saliva
• vitamin B12 released from protein is bound to R binders in the stomach
• Intrinsic factor (IF) is released by parietal cells in the stomach but does not bind vitamin B12 there
• once in the small intestine, pancreatic secretions release vitamin B12 from the R binder
• NOW IF binds to vitamin B12
• in the ileum, the B12-IF complex is recognized and enters the enterocyte by pinocytosis via a highly specialized receptor
• in the ileal enterocyte, vitamin B12 is bound to the transport protein transcobalamin II (TC II) and released into the portal circulation

• vegetarians
• older adults (who have atrophic gastritis)
• people who suffer from malabsorption
• people who've undergone GI surgery
• people w/ Pernicious Anemia

• chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells & loss of stomach acid
• as a result, the stomach's secretion of essential substances like HCl, pepsin, & intrinsic factor is impaired
• this causes digestive problems, vitamin B12 deficiency, megaloblastic anemia (folate), or malabsorbtion of iron --> iron deficiency anaemia

• caused by a loss of gastric parietal cells, which secrete intrinsic factor
• no IF, no subsequent absorption of vitamin B12 in the ileum

• Hematologic (Megaloblastic Anemia)
• Neurologic (system degeneration, peripheral or optic neuropathy)
• Neuropsychiatric (personality changes, impaired memory, depression)

• vitamin B12 deficiency results in neuronal death in the posterior and lateral columns of the spinal cord
• starts as diminished position and vibratory sense in the feet, w/ gradual progression to ataxia, spasticity, & incontinence

• glossitis: a smooth but swollen tongue that may be sore
• might come along with some sort of anemia which can be CAUSED by malabsorption of B12, folate, or iron
• *other symptoms = fatigue & malaise

• 1. CBC (checking a complete blood count will show anemia)
• 2. serum Vit. B12
• 3. methylmalonic acid (accumulates w/out B12 as a cofactor)
• 4. homocysteine (not as conclusive b/c levels can also be affected by folate, Vit. B6 [PLP])

• that most of the RDA for vitamin B12 be consumed in the crystalline form, reflecting the increasing prevalence of atrophic gastritis & difficulty with B12 digestion
• there is no apparent toxicity of vitamin B12 --> there is NO UL

• Vitamin C (ascorbic acid): Scurvy
• Thiamine (B1): Beriberi, Wernicke-Korsakoff
• Niacin (B3): Pellagra, Hartnup's (less severe)
• Folate (B9): Megaloblastic anemia, defects w/ rapid growing tissue
• Cobalamin (B12): anemias, psychotic issues