Biochemistry- need help - ruthur

[ArchivalUser]

Hello, need a little help here. Want to find out how important vitamins are for the step 1 exam. What is more high yield, their metabolisms(enzymes) or the deficiencies? Studing from Kaplan lecture notes. Thanks in advance!

[ArchivalUser]

hi ruthur! i think theres not a single thing that's not HY from vitamins. i integrated concepts from uw and kaplan in my FA and i think i hav pretty much everything related to it.

[ArchivalUser]

Vitamins of Anemia

While the liver stores a 3-4 year supply of vitamin B12, it only stores a 3-4 month supply of vitamin B9 (folate). Thus, while it can take years for a patient to become B12 deficient, it only takes months for a patient to develop a folate deficiency.

Folate is converted to tetrahydrafolate (THF), which is a carbon carrier critical for synthesis of nitrogenous bases (particularly thymine, adenine, and guanine) in nucleic acids, especially in states of rapid cell division (pregnancy, erythropoiesis).

Vitamin B9 (folate) deficiency leads to neural tube defects (e.g. spina bifida, anencephaly) and megaloblastic anemia. Note that in contrast to vitamin B12 deficiency, patients with folate deficiency do not have neurologic manifestations.

Vitamin B9 (folate) is found in leafy green vegetables and can be destroyed by cooking.

A “tea and toast” diet is a classically associated with vitamin B9 (folate) deficiency.
States of high cell synthesis and turnover increase vitamin B9 (folate) demand, including:
• Pregnancy and lactation
• Malignancy
• Hemolytic anemia

Numerous drugs or medications can cause an absolute or relative folate (vitamin B9) deficiency, including:
• Ethanol (suspect B9 deficiency in any alcoholic with macrocytic anemia)
• Oral contraceptives
• Phenytoin
• Trimethoprim/sulfonamides
• Methotrexate

Since folate (vitamin B9) deficiency can cause neural tube defects (e.g. spina bifida, anencephaly), women should begin supplemental folate at least 1 month prior to conception and continue supplementation throughout pregnancy. This timing is critical because the neural tube closes early in gestation, before women may become aware of the pregnancy.

Since anticonvulsants (e.g. valproate, carbamazepine, phenytoin) can lead to decreased serum folate levels, pregnant women on anticonvulsant therapy should be treated with high-dose folate to prevent neural tube defects.

Vitamin B12 (cobalamin) is a cofactor for:
• Methylmalonyl CoA mutase
• Converts methylmalonyl CoA to succinyl CoA
• Metabolism of odd-chain fatty acids, BCAAs
• Methionine synthase
• Transfers methyl groups to homocysteine to form methionine
• Enables single-carbon transfer reactions necessary for nucleotide biosynthesis

Vitamin B12 (cobalamin) is found in animal products (e.g. meat, fish, eggs, dairy).

Vitamin B12 (cobalamin) is synthesized by bacteria. Vitamin B12 cannot be synthesized by plants or animals.

Vitamin B12 (cobalamin) deficiency may occur with:
• Malabsorption (e.g. Diphyllobothrium latum, sprue, enteritis)
• Absence of intrinsic factor (e.g. pernicious anemia or gastric bypass surgery)
• Absence of terminal ileum (due to Crohn disease or resection)
• Vegan diet
• Low gastric acid (due to PPI use)

Vitamin B12 (cobalamin) deficiency leads to macrocytic, megaloblastic anemia and neurologic findings:
• Subacute combined degeneration: degeneration of dorsal (posterior) columns (manifests as decreased vibratory sensation and proprioception), lateral corticospinal tracts (manifests as spasticity), and spinocerebellar tracts (manifests as ataxia)
• Dementia

Vitamin B9 (folate) deficiency can be distinguished from vitamin B12 deficiency on labs by:

Vitamin B9 (folate) deficiency
• Normal methylmalonic acid
• Elevated homocysteine

Vitamin B12 deficiency
• Elevated methylmalonic acid
• Elevated homocysteine

Elevated levels of homocysteine seen in folate and vitamin B12 deficiency cause endothelial cell damage and can result in atherosclerosis and thrombosis.

The treatment for either vitamin B9 (folate) or B12 deficiency is supplementation with the deficient vitamin.

The hematologic symptoms of B12 deficiency can be corrected by folate replacement, e.g., in the case of a misdiagnosis. However, the neurological symptoms will persist due to methylmalonic acid buildup in the myelin sheaths.

[ArchivalUser]

B Vitamins

B vitamins are water soluble; therefore, body stores of B vitamins are quickly depleted (except folate and B12 cobalamin, which are stored in the liver).

Each B vitamin is used in a unique type of biochemical reaction. By understanding the biochemical roles of each B vitamin, one can deduce B vitamin cofactors that are necessary based on the name of the enzyme.

A vitamin B1 (thiamine) derivative, thiamine pyrophosphate (TPP), is an important coenzyme for several reactions, some of which can be remembered with the mnemonic, ATP:
• α-ketoglutarate dehydrogenase
• Transketolase
• Pyruvate dehydrogenase
Vitamin B1 is also a cofactor for branched-chain ketoacid dehydrogenase.

In the United States, thiamine deficiency is most common in alcoholics (due to poor nutrition and that excess alcohol limits the body's ability to absorb and store thiamine.)

Thiamine deficiency may lead to beriberi ("Ber1Ber1") and Wernicke-Korsakoff syndrome.
• Beriberi has a dry (muscle wasting and neuropathy) and wet (dilated cardiomyopathy) component.
• Wernicke-Korsakoff syndrome is composed of Wernicke’s encephalopathy (triad of confusion, ophthalmoplegia, and ataxia) and Korsakoff’s psychosis (memory loss, confabulation and personality change). More information about Wernicke-Korsakoff syndrome can be found in the Alcoholism topic.

Diagnosis of thiamine deficiency can be confirmed by an increase in RBC transketolase activity that occurs after thiamine is supplemented.

Vitamin B2 (riboflavin): key component of the flavin cofactors of flavoproteins; these proteins participate in redox reactions. Flavin cofactors include:
• Flavin mononucleotide (FMN): component of NADH dehydrogenase, aka complex I of the electron transport chain
• Flavin-adenine dinucleotide (FAD): component of succinate dehydrogenase of the TCA cycle, aka complex II of the electron transport chain

Vitamin B2 (riboflavin) deficiency causes:
• Cheilitis (cracked angles of the mouth)
• Glossitis with a magenta-colored tongue
• Corneal vascularization

Vitamin B6 (pyridoxine) is a cofactor for:
• Transamination
• Decarboxylation
• Glycogen phosphorylase
Vitamin B6 is also a cofactor for other reactions as well.

Vitamin B6 (pyridoxine) is needed to produce many different compounds, and is a cofactor in steps of many different pathways. Pyridoxine is a cofactor for the following 4 neurotransmitter synthesis reactions:
• Glutamate → GABA
• Tryptophan → Serotonin
• DOPA → Dopamine (dopamine can then go on to form norepinephrine and epinephrine)
• Histidine → Histamine

Medications that can induce Vitamin B6 deficiency include oral contraceptives and isoniazid.

Vitamin B6 (pyridoxine) deficiency causes:
• Neurological pathology: Peripheral neuropathy and convulsions (due to defective neurotransmitter synthesis).
• Anemia: Sideroblastic anemias due to defective heme synthesis.

A core treatment in Parkinson's disease is L-DOPA therapy. Supplemental vitamin B6 can convert L-DOPA to dopamine peripherally (as opposed to in the CNS), rendering treatment less efficacious.

Vitamin B6 (pyridoxine) is a cofactor in both cystathionine and heme synthesis. Further discussion regarding these pathways is given in the corresponding topics.

Vitamin B7 (biotin): cofactor in several carboxylation reactions including:
• Acetyl-CoA carboxylase: converts acetyl-CoA (2C) to Žmalonyl-CoA (3C) in fatty acid synthesis
• Pyruvate carboxylase: converts pyruvate (3C) to oxaloacetate (4C) in gluconeogenesis
• Propionyl-CoA carboxylase: converts propionyl-CoA (3C)Ž to methylmalonyl-CoA (4C) in the metabolism of odd-chain fatty acids

Biotin deficiency causes:
• Dermatitis
• Alopecia
• Enteritis

Although relatively rare, biotin deficiency can be caused by antibiotic use or excessive consumption of raw egg whites, which can be seen in individuals who are bodybuilders or boxers (e.g., Rocky Balboa).

Raw egg whites contain avidin, which binds and sequesters biotin within the GI tract. In the presence of avidin, biotin is eliminated with the feces rather than absorbed. Heating egg whites denatures avidin, rendering it unable to bind biotin.

Vitamins B9 (folic acid) and B12 (cobalamin) are discussed in the "Vitamins of anemia" topic.

Vitamin B3 (niacin) is a precursor for NADH and NADPH. It is used pharmacologically to increase HDL and decrease LDL, typically as alternative or supplemental therapy to other first-line anti-lipid medications.

Niacin deficiency leads to glossitis and may lead to pellagra in severe deficiency. Pellagra is a syndrome of the "3 D's of B3 deficiency," which are:
• Diarrhea
• Dermatitis (classically in a "necklace" distribution around the neck)
• Dementia

Niacin can be used to treat hyperlipidemia; side effects in this setting include prostaglandin-induced skin flushing (avoid with aspirin coadministration) and the potential development of hyperuricemia and hyperglycemia.

Niacin may also be endogenously synthesized from tryptophan in a process using vitamin B6. Prolonged and stark vitamin B6 deficiency may lead to niacin deficiency as well.

Carcinoid syndrome is a complication of carcinoid tumors (most commonly of the small bowel) in which serotonin is systemically elaborated in great excess. Tryptophan is compensatorily shunted to make serotonin, decreasing conversion to niacin. Therefore, niacin deficiency is a potential complication of carcinoid syndrome.

Hartnup disease is an autosomal recessive defect in intestinal and renal transporters for neutral amino acids. This causes tryptophan excretion in urine and leads to pellagra.


Vitamin B5 (pantothenic acid) is needed to form coenzyme-A (CoA).

Vitamin B5 deficiency is rare. Clinical manifestations of deficiency include:
• Dermatitis
• Enteritis
• Alopecia
• Adrenal insufficiency

[ArchivalUser]

Vitamin C

Vitamin C (ascorbate) is a water soluble vitamin.

Vitamin C is an important hydrophilic antioxidant (versus vitamin E, which is an important hydrophobic antioxidant)

Vit C serves as a cofactor for prolyl-4-hydroxylase and lysyl hydroxylase, an enzyme involved in collagen synthesis.

Stable collagen cannot form without proline and lysine hydroxylation. This hydroxylation take place in the ER.

Hydroxylation of proline secures the collagen chains in triple helix formation.

The subsequent hydroxylation of lysine is required for cross-linking.

Other roles of Vitamin C:
• Cofactor for dopamine hydroxylase (dopamine → norepinephrine)
• Reduces iron from Fe3+ → Fe2+, facilitating absorption in the duodenum

Excess consumption of Vitamin C can lead to calcium oxalate nephrolithiasis.

Excess consumption of Vitamin C can further increase the risk of iron toxicity in patients already predisposed to iron toxicity. Those at risk includes patients that receive frequent transfusions and those with hereditary hemochromatosis.

Deficiency of vitamin C leads to scurvy due to defective collagen synthesis.

Clinical manifestations of scurvy include:
• Swollen, spongy and purplish gums that bleed often
• Bleeding into the skin (bruising)
• Red spots under skin from burst capillaries (petechiae)
• Loose teeth
• Bulging of the eyes (proptosis)
• Anemia
• Dry, brittle hair that curls ("corkscrew" hair)
• Slow wound healing
• Bleeding into the joints (hemarthrosis) and muscles, which causes swelling over the bones of the arms and legs

[ArchivalUser]

Fat Soluble Vitamins

Vitamins A,D,E,K are fat soluble vitamins that are transported in chylomicrons, and stored in liver or adipose tissue.
• fat-soluble vitamins are more likely to reach toxic levels than water-soluble vitamins
• deficiencies of fat soluble vitamins can occur any time fat malabsorption occurs, for example: malabsorption syndromes (e.g. tropical sprue), pancreatic insufficiency, and resected ileum.

Vitamin E: antioxidant and scavenger of free radicals that protects polyunsaturated fats and fatty acids in cell membranes from lipid peroxidation and protects LDL from oxidation.

Clinical manifestations of vitamin E deficiency include:
• Hemolytic anemia
• Acanthocytosis due to free radical-induced RBC membrane injury
• Ataxia due to posterior column, spinocerebellar tract demyelination
• Neuromuscular disorders

Neurologic manifestations of vitamin E deficiency can mimic those of vitamin B12 deficiency, but vitamin E deficiency occurs without elevated methylmalonic acid levels or megaloblastic anemia.

Excess (taking megadoses of vitamin E): decreased synthesis of vitamin K-dependent coagulation factors in the liver, thereby working synergistically with warfarin.

Vitamin A is an antioxidant that also participates in:
• Retinal phototransduction
• Differentiation of specialized epithelium
• Prevention of squamous metaplasia

Sources of vitamin A:
• Liver
• Egg yolks
• Leafy greens
• Carrots

Deficiency: night blindness, squamous metaplasia leading to skin abnormalities (follicular hyperkeratosis), eye abnormalities (Bitot's spots → buildup of keratin debris in conjuctiva), lung abnormalities (bronchitis, pneumonia)

Acute vitamin A toxicity causes:
• Nausea
• Vomiting
• Visual disturbances
• Vertigo

Chronic vitamin A toxicity causes:
• Hepatoxicity, hepatomegaly
• Dry skin
• Alopecia
• Arthralgias
• Pseudotumor cerebri

Three conditions that are commonly treated by vitamin A and its derivatives include:
• Acute promyelocytic leukemia: all-trans retinoic acid (systemic)
• Acne vulgaris: all-trans retinoic acid, aka tretinoin (topical)
• Measles: vitamin A (esp. in malnourished children)

Before oral isotretinoin (cis retinoic acid) is prescribed for severe cystic acne, women must have a pregnancy test because high doses of Vitamin A are highly teratogenic (birth defects include cleft palate, cardiac abnormalities, low IQ scores and extremely high risk for spontaneous abortions)

Vitamin D2 (ergocalciferol, found in plants) and vitamin D3 (cholecalciferol): increases intestinal absorption of calcium and phosphorous and renal absorption of calcium. It also plays a role in PTH-induced osteoclast activation and resorption of bone.

Sources of vitamin D include:
• Liver
• Egg yolk
• Saltwater fish
• Vitamin D fortified foods (milk)

Vitamin D3 is made by skin after sunlight exposure (although some foods are now fortified with synthetic D3).

Endogenous vitamin D is produced by photoconversion of 7-dehydrocholesterol to vitamin D3 in sun-exposed skin (most important source).

Next, vitamin D is hydroxylated in the liver to produce calcidiol (25-hydroxycholecalciferol) by the P450 system.

Calcidiol is then hydroxylated to the active form, calcitriol (1,25-dihydroxycholecalciferol) in the kidneys by the enzyme 1-α-hydroxylase.

Causes of vitamin D deficiency:
• Renal failure (most common cause): deficiency of 1-α-hydroxylase
• Inadequate exposure to sunlight: decreased synthesis of vitamin D3
• Fat malabsorption: cannot reabsorb fat soluble vitamins
• Chronic liver disease: unable to carry out first hydroxylation of vitamin D3
• Enhanced liver cytochrome P450 system (e.g. alcohol, phenytoin, barbiturates): increased conversion of 25-hydroxycholecalciferol into inactive metabolite
• Primary hypoparathyroidism: need PTH to enhance activity of 1-α-hydroxylase
• Type 1 vitamin D-dependent rickets: deficiency of 1-α-hydroxylase
• Type 2 vitamin D-dependent rickets: deficiency of vitamin D receptors

Vitamin D deficiency causes:
• Rickets in children (imperfect calcification, softening, and distortion of the bones classically resulting in bowed legs)
• Osteomalacia in adults (soft bones and bone pain).
• Hypocalcemic tetany (decreased extracellular calcium levels cause increased excitability of voltage gated sodium channels, leading to increased muscle contractions)

Vitamin D toxicity leads to:
• Hypercalcemia
• Renal calcium stones
• Nausea and vomiting

Vitamin K ("Koagulations-vitamin" in German) is a required cofactor for the gamma-carboxylation of glutamate residues, which is required for the activation of:
• 4 pro-coagulants: clotting factors IX, X, VII, II (prothrombin)
• 2 anti-coagulants: proteins C and S

Vitamin K is obtained from green leafy vegetables (supply K1, phylloquinone) and from bacterial synthesis in the colon (supply K2, menaquinone).

Since vitamin K is synthesized by intestinal flora and neonatal intestines are not yet colonized by bacteria, infants are given a vitamin K injection at birth to prevent hemorrhagic disease of the newborn. (Vitamin K is also not in breast milk).

Vitamin K deficiency leads to hemorrhage with:
• Prolonged prothrombin time (PT)
• Prolonged activated thromboplastin time (aPTT)
• Normal bleeding time

[ArchivalUser]

Ignore the letter Z that appears twice in the Biotin discussion. B7