Biochemistry

Blood vessels:
Lead poisoning: o The zinc-containing -aminolevulinate dehydratase and ferrochelatase are enzymes in the heme biosynthetic pathway that are inactivated by lead. Thus in lead poisoning, -ALA and protoporphyrin IX accumulate, and the production of heme is decreased, leading to microcytic anemia secondary to a lack of hemoglobin. (typically in old houses) o Pyridoxal phosphate is a necessary cofactor in the synthesis of -aminolevulinic acid.

Hematology:
Leading and lagging strands: the lagging strand is synthesized discontinuously and is composed of short stretches of RNA primer plus newly synthesized DNA segments called Okazaki fragments. Thus the lagging strand requires the repetitive action of DNA ligase to join this continuous stretches of DNA at the completion of replication. (Is the main difference in the synthesis of 5-3 and 3-5 strands) Okazaki fragments are short stretches of RNA primers plus newly synthesized DNA that account for the discontinuous synthesis of DNA with subsequent linking on the lagging strand during 3-5 replication.

Stop codons: UGA, UAG, and UAA are stop codons and mutations producing abnormally placed stop codons are called nonsense mutations. (UCA->UGA) Chloride shift: carbonic anhydrase activity within erythrocytes forms bicarbonate from CO2 and water. Many of the bicarbonate ions diffuse out of the RBC into the plasma. To maintain the electrical neutrality chloride ions diffuse into the RBC to take their place. This is called chloride shift, and is the principal cause of high RBC chloride content in venous blood. CO binds to hemoglobin with an affinity that is 220 times that of oxygen for hemoglobin. The binding of CO and O2 to hemoglobin are reversible. CO therefore competes with O2 for binding on the heme iron of hemoglobin. HMP shunt: o Transketolase and transaldolase carry out the nonoxidative reactions of HMP shunt. Some cells do not use oxidative phase reactions to produce cytosolic NADPH, but all cells can synthesize ribose from fructose-6-phosphate using the nonoxidative reactions.

Glucose 6-phosphate dehydrogenase deficiency is a defect in HMP shunt that impairs glutathione reduction due to the failure to produce NADPH. Glutathione reductase deficiency causes a similar clinical picture and is pathologically similar to G6PD deficiency. Pyruvate kinase deficiency: it causes hemolytic anemia due to failure of glycolisis and resultant failure to generate sufficient ATP to maintain erythrocyte structure. (E.g. a pt with splenomegaly and low pyruvate kinase activity in blood, the cause is work hypertrophy). A pt with recurrent abdominal pain and anxiety has had marked improvement in the symptoms after intravenous administration of a heme preparation. This improvement is due to significant repression of -aminolevulinate synthase. (Deficiency of this enzyme results in Porphyria). Heme catabolism: o Heme catabolism: heme oxygenase converts heme to biliverdin, a pigment that causes the greenish color to develop in bruises several days after the injury. o Glucose 6-phosphate dehydrogenase deficiency is a common x-linked disorder of the hexose monophosphate pathway that results in episodes of hemolytic anemia due to oxidative stress. Letter C.

Methemoglobin and cyanide: o Amyl nitrites are oxidizing agents that are effective in the tx of cyanide poisoning due to their ability to cause methemoglobinemia. o Base excision repair is used to correct defects in single bases induced spontaneously or by exogenous chemicals. In this process glycosylases remove the defective base, and the correspondent sugar phosphate is cleaved and removed by endonuclease, followed by the action of lyase. DNA polymerase then replaces the missing nucleotides and ligase reconnects the DNA strand. Glycosylase->endonuclease->lyase->DNA polymerase->ligase Methemoglobinemia: causes dusky discoloration to the skin (similar to cyanosis), and because Methemoglobin is unable to carry oxygen, a state of functional anemia is induced. Partial pressure of oxygen in the arterial blood will be unchanged. High affinity hemoglobinopathies: the P50 is the partial pressure of oxygen where hemoglobin is 50% saturated. A decrease in P50 means that hemoglobin has an increased oxygen affinity. An increased oxygenaffinity of hemoglobin causes less oxygen to be released in the tissues, and results in hypoxia, then reflects polycythemia.

The individual subunits of the hemoglobin molecule are structurally analogous to myoglobin; if separated, the subunits will demonstrate a hyperbolic oxygen-dissociation curve similar to that of myoglobin.

A left shift of the hemoglobin oxygen curve indicates increased hemoglobin O2 affinity and can be caused by increased pH, decreased 2, 3-DPG, and decreased temperature. A left-shift of the oxygen-dissociation curve means that O2 is relatively less available to tissues. (Severe hypothermia)

Oxygen dissociation curve:

The thalassemias result from mutations that cause defective mRNA processing, which leads to deficiency of certain protein chains required for hemoglobin synthesis.

Mature erythrocytes lose their ability to synthesize heme when they lose their mitochondria. Mitochondria are necessary for the first and final three steps of heme synthesis. HbF dominates in newborns. It consists in two gamma protein subunits (2 2); it has a high affinity for oxygen and is produces during the final seven months of gestation. Switching to HbA (22) occurs during the first six months of life. o HbF contains -globin instead of -globin. Pts with homozygotic -thalassemia are asymptomatic at birth due to the presence of -globins and HbF. (e.g. an asymptomatic pt that when turning 6 months develop transfusion-dependent hemolytic anemia). o Fetal hemoglobin binds oxygen with a higher affinity due to its inability to interact with 2, 3biphosphoglycerate. So a single amino acid residue replacement (serine instead of histidine) in the hemoglobin -subunit results in poor interaction with 2, 3-DPG.

HbS contains (sickle cell anemia) valine in place of glutamic acid in the 6 amino acid position of the beta subunit. o This promotes hydrophobic interaction among hemoglobin molecules and results in polymerization of HbS molecules and red blood cell distortion. o It aggregate in the deoxygenated state (would aggregate upon oxygen unloading). HbS polymers form fibrous strands that reduce RBC membrane flexibility and promote sickling. It occurs under all conditions associated with anoxia including low pH and high 2, 3-DPG. HbC disease is caused by a substitution (lysine instead of glutamic acid). Is a missence mutation.

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SCA mutation: Exertional dyspnea, pneumonia resulting in life-threatening acute chest syndrome, and recurrent abdominal and bone pain are clinical features of sickle cell anemia. Sickle cell anemia results from a point mutation that causes valine to substitute for glutamic acid in the sixth position of the bglobin chain of hemoglobin. Folate deficiency: inhibits the formation of deoxythymidine monophosphate (dTMP), which limits DNA synthesis and promotes megaloblastosis and erythroid precursor cell apoptosis. Because thymidine supplementation can moderately increase dTMP levels, it can reduce erythroid precursor cell apoptosis. Vitamin K resistance of glutamine residue carboxylation is essential for some clotting factor production. The symptoms of difficulty swallowing, and disfigured finger nails (koilonychias) are specific for iron deficiency anemia.

Cardiology:
Studies have suggested that increased serum levels of homocysteine may predispose to thrombosis. Folic acid and vit B12 supplementation can decrease homocysteine levels according to the mechanism of homocysteine converted to methionine using methylcobalamin and methyl tetrahydrofolate. Homocystinuria: o It is caused by cystathionine synthetase deficiency. Pts are at high risk of thromboembolism. About 50% respond to high doses of B6 (pyridoxine). o They have skeletal characteristic of Marfan like syndrome. o Is a condition that leads to hypercoagulability and premature atherosclerosis (8 yld boy with acute myocardial infarction). This pts cannot form cysteine from homocysteine; thus cysteine is essential in the diet of this pts.

Head and Neck:

Nucleosomes: are structural subunits present inside the nucleus composed of nuclear proteins called histones. Histone H1 is located outside of the nucleosome core and helps package Nucleosomes into more compact structures.

Neurology:
Tetrahydrobiopterin is a cofactor in the synthesis of tyrosine, dopa, and serotonin, as well as nitric oxide. Impaired Tetrahydrobiopterin synthesis in a pt would lead to serotonin deficiency. Ureas nitrogen is derived from NH3 and aspartate in the urea cycle.

Propionic acidemia- is clinically characterized by: poor feeding, vomiting, hypotonia, lethargy, dehydration, and an anion gap acidosis. Propionic acid is the intermediate in the catabolism of branched chain amino acids, such as valine, threonine, methionine, isoleucine, cholesterol, and odd-chain fatty acids, and is not produced during the catabolism of other amino acids. A pt with hyperphenylalaninemia at birth is placed in a phenylalanine restricted diet. After that his serum prolactin levels are elevated because the enzyme dihydrobiopterin reductase is deficient. (Seen in Phenylketonuria). Methylmalonic acidemia results from a defect in the isomerization reaction that transforms methylmalonil CoA to succinil CoA, prior to succinil CoA entering the TCA cycle. (Newborn with lethargy, vomiting, and tachypnea soon after birth.) A defect in the peroxysomes, you will find in cultured fibroblasts from a infant that is suffering hypotonia and seizures will show an impaired ability to oxidize very long chain fatty acids and phytanic acid. Impaired transport of Ornithine from the cytosol to the mitochondria results in urea cycle defects which cause neurological damage due to the accumulation of ammonia. Protein restriction would improve this condition.

N-acetylglutamate is an essential activator of Carbamoyl phosphate synthase I and is formed by the enzyme N-acetylglutamate synthetase from the precursor acetyl- CoA and glutamate.

Acute intermittent Porphyria: o Acute onset of abdominal pain, nausea, and confusion. Urine normal in color but turns dark upon standing. o Glucose loading decreases porphyrin synthesis by repressing ALA synthase activity, thus alleviating the abdominal pain and neuropsychiatric manifestations. Wernicke syndrome: o Triad of: ophthalmoplegia, ataxia, and confusion. A focus of hemorrhage and necrosis in the mamillary bodies and periaqueductal grey matter is found on autopsy. o Caused by thiamine (B1) deficiency, which can be dx by measuring erythrocyte transketolase.

Gastrointestinal:
Lac operon: o Is the genetic system in the E. coli genome that codes for proteins required for the metabolism of lactose. o Glucose induced decreased adenylate cyclase activity leads to low intracellular concentrations of cAMP, leading to decreased expression of the structural genes of the lac operon. (e.g. E. coli are grown in a medium containing lactose, once glucose is added, the bacteria stopped fermenting lactose due to a low cellular level of cAMP). o Bacterial mRNA can be polysistronic, meaning that one mRNA cods for several proteins. (There one mRNA coding for both enzymes). Protein digestion: trypsinogen is activated to trypsin by duodenal enteropeptidase. Trypsin is essential for protein digestion and absorption in two ways. It degrades complex peptides to dipeptides and amino acids, and it activates other proteases such as carboxypeptidase, elastase and chymotrypsin. (e.g. and infant who fails to gain weight has no enteropeptidase activity on the surface of the duodenal epithelium, formation of trypsin is most likely impaired). Essential fructosuria: unlike hereditary fructose intolerance and classic galactosemia, essential fructosuria is a benign disorder resulting from a defect or deficiency in the enzyme fructokinase.

Secondary lactase deficiency can occur after viral gastroenteritis or other diseases that disturb the intestinal epithelium. This disease causes abdominal distension, flatulence and diarrhea after lactose ingestion. Letter E.

Pulmonology:
Hypoxia- induced lactic acidosis is caused by a low activity of pyruvate dehydrogenase (oxidative phosphorylation pathway) and a high activity of lactate dehydrogenase. Lysine oxidase: elastins plasticity and ability to recoil upon release of tension is due to interchain crosslink involving lysine. Streptomycin: inhibits the initiation of protein synthesis by binding to and distorting the structure of the prokaryotic 30S ribosomal subunit. (e.g. M. tuberculosis)

Hepatobiliary:
Eukaryotic cell DNA replication: multiple origins of replication make eukaryotic DNA synthesis quick and effective despite the large size of the genome compared to that of prokaryotic organisms. Pompes disease: acid maltase (acid -glucosidase) deficiency leads to glycogen accumulation within lysosomal vesicles. Clinical manifestations of this disease: hepatomegaly, cardiomegaly, macroglossia, hypotonia, and mental retardation in its more severe form. Galactosemia: o Galactiol accumulates in lens of pts with galactosemia and causes osmotic damage leading to cataract formation. It is formed from excess circulating galactose in galactosemia by aldose reductase. o Classic galactosemia results from deficiency of galactose-1-phosphate uridyl transferase; this is the M.C. cause. Findings: vomiting, lethargy, and failure to thrive soon after breastfeeding is begun. Letter C

Hypoglycemia in the setting of a high intracellular ratio of NADH TO NAD can occur when a metabolic fuel other than glucose (e.g. ethanol) is present. (pt have been consuming large volumes of alcohol) Several tissues use triglyceride breakdown products as intermediates in energy generation and glucose synthesis. Glycerol kinase is a liver-specific enzyme that facilitates those reactions.

Impaired FA oxidation: hypoglycemia after prolonged fasting with inappropriately low levels of ketone bodies suggests impaired -oxydation. Acetyl-CoA dehydrogenase catalyzes the first step in the oxydation pathway. Acetyl-CoA: is an important allosteric activator of Gluconeogenesis that acts by increasing the activity of pyruvate carboxylase. Fructose intolerance: o Aldolase B participates in fructose metabolism. Deficiency of Aldolase B results in fructose intolerance; fructose and sucrose should be removed from diet. (sucrose= fructose + glucose) Glucose metabolism: glycogenolysis provides immediate energy for strenuous muscle contraction; myophosphorylase deficiency leads to failure of glycogenolysis and clinical manifestations of decreased exercise tolerance, myoglobinuria and muscle pain with physical activity. Failure in the A pathway:

HMP shunt: in certain metabolic conditions, hepatocytes increase the conversion of glucose to ribulose-5phosphate. This condition supplements cholesterol synthesis. Carnitine deficiency: impairs fatty acid transport into mitochondria, restricting ketone body production. So an infant dx with Carnitine wasting and deficiency, would also have deficient synthesis of acetoacetate. Ketone utilization: erythrocytes and other cells lacking mitochondria cannot utilize ketone bodies for energy. While hepatocytes have mitochondria, they also cannot utilize them because they lack the enzyme succinil CoA-acetoacetate CoA-transferase.

Hepatobiliary Enzymes:
Debranching enzyme deficiency: (Cori disease) o Leads to incomplete glycogen degradation. o Findings: growth retardation, hepatomegaly, and hypoglycemia. Accumulation of small chain dextrin-like material within the cytosol of the hepatocytes. Laboratory testing revealing high arginine levels in plasma and cerebrospinal fluid, the enzyme deficient in this pt is involved in the production of urea. Pt suffers from Arginase deficiency. Transketolase: enzyme of the pentose phosphate pathway that uses thiamine (B1) as a cofactor. All of these reactions occur in the cytoplasm, so the enzyme will remain and homogenate that only contains cytosol and proteins.

Disorders of the urea cycle can result from defects of any of the following enzymes:
o o o o o o Ornithine transcarbamoylase (is the M.C. results in severe neurological due to high blood and tissue ammonia levels. Increased urine orotic acid excretion is typical. Carbamoyl phosphate synthetase Argininosuccinic acid synthetase Argininosuccinic acid lyase Arginase N-Acetylglutamate synthetase

Citric acid cycle: Letter B

--ketoglutarate dehydrogenase requires thiamine as a cofactor. Administration of glucose to thiamine deficient pts, such as alcoholics, will result in Wernicke encephalopathy due to increase in thiamine demand.

Pantothenate: the biologically active form of pantothenic acid is coenzyme A, which binds to oxaloacetate in the first step of TCA cycle to form citrate and then succinil-CoA. Is needed for the oxaloacetate to citrate conversion.

Lipoic acid: is a cofactor of several enzymes: PDH (deficiency results in lactic acidosis), -ketoglutarate DH and branched-chain ketoacid DH (deficiency results in maple syrup urine disease).

Hepatobiliary Amino Acids:

Amino groups are released during the metabolism of amino acids. These amino groups are primarily transferred to -ketoglutarate to form glutamate, the primary carrier of ammonia from liver. (Before conversion to glucose, the alanine transfers its amino groups to -ketoglutarate).

Renal: Amino Acids

Maple syrup urine disease: o Caused by a defect in -keto acid dehydrogenase. o Classically results in dystonia, poor feeding, and maple syrup scent in pt urine (first few days of life). o Leucine must be restricted in pt diet. o Some pts with this disease may respond to high dose of thiamine (B1) supplementation. Glycine: o Is the most abundant amino acid in the collagen molecule. So it is more avidly consumed by the fibroblasts.

Musculoskeletal:
Collagen:

o C-terminal propeptide removal is a process that occurs outside of the fibroblasts during collagen o
synthesis. Terminal peptide cleavage and collagen fibril crosslinking occurs in the extracellular space.

Glycogen degradation is coupled with skeletal muscle contraction due to Ca mediated myophosphorilase activation. IP3 begins with hormone binding and G-protein activation leading to activation of phospholipase C. Phospholipase C forms diacylglycerol and IP3 from phospholipids, and IP3 causes an increase in intracellular Ca, which then activates protein kinase C. Phenylketonuria: o Common in pts with Scandinavian descent. o Deficiency of phenylalanine hydroxylase, responsible for the conversion of phenylalanine to tyrosine. o Tyrosine becomes an essential amino acid in pt. o Pts develop mental impairment, seizures, hyperactivity, gait abnormalities, decreased pigmentation of hair and skin, eczema, mousy odor. (Infant with severe mental retardation, seizures, and dies from a respiratory infection, autopsy reveals pallor o the substantia nigra, locus ceruleus, and vagal nucleus dorsalis). o Deficiency of dihydrobiopterin reductase causes high prolactin serum levels. Alkaptonuria: o Benign disorder of tyrosine metabolism. o Is an autosomal recessive, were the conversion of tyrosine to fumarate is prevented. o Caused by the deficiency of homogentisic acid o Benign childhood disorder that matures to arthritis in adult life. o Findings: urine sample turned black on the way to the lab, and ochronosis (blue-black pigment in ears, nose, and cheeks). (M.C. in sclera and ear cartilage). Marfan syndrome: o Due to a defect in fibrillin, a glycoprotein abundant in the lens, periosteum and aortic media. o Findings: long thin extremities, loose joints, arachnodactilyty; ocular abnormalities (dislocation of lens); cardiovascular abnormalities (ascending aortic aneurysm, aortic dissection, and mitral valve prolapsed).

Dermatology:
Consequences of aging, fine skin wrinkles appear secondary to the decreased synthesis and net loss of dermal elastin and collagen fibril production. After UV damage, pyrimidime dimmers are formed in cellular DNA, which are recognized by a specific endonuclease which initiates the process of repair by nicking the strand at the thymine dimmer. This action signals the removal and replacement of this damage DNA. (specific endonuclease nicks the damage DNA strand).

Porphyria cutanea tarda: deficiency of uroporphyrinogen decarboxylase leads to photosensitivity which causes vesicle and blister formation on sun-exposed areas as well as edema, pruritus, pain, and erythema.

Hartnup disease: o Result in niacin deficiency due to an excess loss of dietary tryptophan resulting from defective intestinal and renal tubular absorption of that amino acid. o Findings: ataxia, episodic erythematous and pruritic skin lesions, loose stool. o Lab findings: loss of neutral aromatic amino acids in the urine.

Endocrinology:
Insulin resistance: aberrant serine and threonine residue phosphorylation by tyrosine kinase leads to insulin resistance. These aberrant phosphorylations can occur in the presence of TNF-alpha, cathecholamines, glucocorticoids, and glucagon. TNF-alpha causes a defect in serine residue phosphorylation. Insulin signal transmission: protein kinase-1 promotes a rapid increase in intracellular glycogen stores and a decrease in glucose release into the blood. Glucokinase mutation and diabetes: Glucokinase is a glucose sensor within pancreatic beta cells. Inactivating mutations of the enzyme result in mild hyperglycemia that can be exacerbated by pregnancy. Gluconeogenesis: after overnight fasting Gluconeogenesis is the principal source of blood glucose. It uses many of the bidirectional enzymes involved in the process of glycolisis. The initial committed step of Gluconeogenesis involves the conversion of pyruvate to oxaloacetate to phosphoenolpyruvate. Citric acid cycle: during starvation the liver oxidizes fatty acids and produce glucose (Gluconeogenesis) for peripheral tissues. The product of succinyl CoA is used as a phosphate source for phosphoenolpyruvate in Gluconeogenesis. Letter C.

LDH and glycolisis: inhibition of lactate dehydrogenase in strenuously exercising skeletal muscles would eventually leads to an inhibition of glycolisis due to intracellular depletion of NAD. Sorbitol metabolism: aldose reductase converts glucose into Sorbitol, which is further metabolized into fructose by Sorbitol dehydrogenase. (fructose is the product of Sorbitol oxidation) Hereditary fructose intolerance: Aldolase B deficiency causes hereditary fructose intolerance. (Manifestation when cereals and juice are introduced to diet). Fructose 1 phosphate: it has the highest rate of metabolism in the glycolytic pathway. Other sugars enter glycolisis before this rate limiting step and are therefore metabolized more slowly. Fructose 2-6 biphosphate: liver cells that demonstrate a high concentration of fructose 2,6-biphosphate have a low rate of alanine->glucose conversions.

In pts with essential fructosuria, metabolism of fructose by hexokinase to fructose-6-phosphate is the primary method of metabolizing dietary fructose; this pathway is not significant in normal individuals. Thyroid hormones have a nuclear receptor. They alter gene transcription by binding to receptors situated inside of their nucleus. Protein kinase A: responsible for the intracellular effects of the G-protein/adenylate cyclase second messenger system. It controls the release of glucose in the blood. Protein kinase C: an agent that specifically blocks the interaction of inositol triphosphate with its intracellular receptor would most likely decrease the activity of protein kinase C. B -cell physiology: ATP is the regulatory substance that stimulates KATP channel closure in insulin-producing pancreatic beta cells. Cortisol: binds to an intracellular receptor and increases Gluconeogenesis in the liver. Phenylethanolamine-N-methyltransferase is responsible for the synthesis of epinephrine, and is under the control of cortisol. JAK/STAT pathway: colony stimulating factors, prolactin, growth hormones and cytokines utilize tyrosine kinase-associated receptors and the (Janus kinase) JAK/STAT signaling pathway. Pyruvate dehydrogenase deficiency: o A disease with multiple presentations ranging from neonatal death to mild episodic syndrome in adulthood. o Prevents the conversion of pyruvate to acetyl CoA, pyruvate is shunted to lactic acid resulting in lactic acidosis in the pts. o Lysine and Leucine are exclusively ketogenic and would not increase the blood lactate levels in these pts. Steroid receptors: o When inactive they are bound to heat shock protein 90 (hsp90) and 56 (hsp56). They are release when the receptor binds the steroid hormone. (e.g. a colony of cells exposed to high-dose of cortisol in an experimental setting, intracellular substance that will increase immediately after exposure is unbound hsp90) Endocrinology Genetics:

RNA synthesis: the nucleolus is the site of RNA synthesis. (letter B) Mitochondrial DNA: they resembling prokaryotic DNA and being derive completely from the mother, mitochondrial DNA is the most common non nuclear DNA found in eukaryotic cells. Letter D

Integral membrane proteins: contains transmembrane domains composed of alpha helices with hydrophobic amino acid residues such as valine, alanine, isoleucine, methionine, and phenylalanine. Its function is spanning the cellular membrane.

Oncology:
Xeroderma pigmentosum: endonuclease is the nonfunctional enzyme in this disease. Exposure to radiation, including therapeutic and palliative radiation therapy, induces DNA damage through DNA double-strand fractures and the formation of oxygen free radicals. (double strand DNA breaks)

General Genetics:
CAA is the anticodon of the tRNA that would insert the last amino acid into the polypeptide chain. Epidermal basal cells have TTAGGG at the 3-end of the chromosomes. Helicase unwinds DNA at the replication fork. Letter E.

DNA polymerase I: o Is a bacterial enzyme that has the ability to remove RNA primers during DNA replication. If this enzyme is not functional, then there is no prokaryote DNA replication. o 5 to 3 exonuclease activity is used to remove the RNA primer and remove damage DNA. DNA polymerase III- it removes improper base-pair nucleotide during replication. All three prokaryotic DNA polymerases have proof reading activity and remove mismatched nucleotides via 3 to 5 exonuclease activity.

The tRNA structure. The site responsible for amino acid binding is at the 3 end. Letter A

Turner syndrome: o Chromosomes in the epithelial cells contain regions with methylated DNA which is associated with low transcription activity. Frame shift mutation: they alter the reading frame of the genetic code, resulting in the formation of nonfunctional proteins.

HbC disease is caused by a substitution (lysine instead of glutamic acid). Is a missence mutation.

Vitamins:
Vitamin A: o Deficiency characterize by night blindness, xerophthalmia, and vulnerability to infection (especially measles). o Overuse cause papilledema, dry skin, hepatoesplenomegaly. Vitamin C: o its deficiency causes scurvy. Findings: bleeding gums, superiosteal hematomas, bleeding into joint space, gingival swelling, anemia, popular rashes, impaired wound healing. o Hydroxylation of proline and lysine residues in the collagen precursor occurs in the rough endoplasmic reticulum (RER) and requires vitamin C as a cofactor. Vitamin D: o In breast fed newborns vit D and K is typically insufficient to meet their nutritional needs; so it should be supplemented, especially vit D in dark skinned newborns.

Biotin: o It acts as a CO2 carrier on the surface of the carboxylase enzyme and is necessary for numerous conversions, including pyruvate to oxaloacetate. Excessive ingestion of avidin (found in egg whites) has been associated with biotin deficiency. Niacin (B3): (nicotinic acid) o It can be synthesized endogenously from *tryptophan, which is a NDA+ precursor enzyme*. o Deficiency is characterized by pellagra (dementia, dermatitis, and diarrhea), and Hartnup disease. Thiamine (B1): o Deficiency is associated with infantile and adult beriberi, and in Wernicke syndrome. o Usually found in alcoholics (dry and wet), in wet beriberi you found cardiac involvement (cardiomegaly, cardiomyopathy, congestive heart failure, peripheral edema, tachycardia). Riboflavin (B2): o Deficiency can be seen in alcoholics, and severe malnourished. Finds: painful lesions on the lips and at the corners of the mouth. o Is a precursor of the coenzyme flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). FAD participates in tricarboxylic acid cycle as a coenzyme of succinate dehydrogenase, which converts succinate into fumarate. Pyridoxine (B6): o Serve as cofactor in amino acid transamination and in decarboxylation reaction. E.g. oxaloacetate forma aspartate while reacting with glutamate with the help of pyridoxine. Cobalamin (B12): o Deficiency is frequently associated with pernicious anemia. Presentation is older, mentally slow women who is lemon colored (anemic & icteric), has a smooth, shiny tongue indicative of atrophic glossitis, and demonstrates shuffling broad-base gait. o Hepatic stores on B12 may last up to several years. o It deficiency causes Homocystinuria, due to impaired methionine resynthesis.

TCA cycle:

Metabolism of methionine: