Transcript USMLE STEP 1 Review: Week 3, Biochemistry

Chase Findley, MSIV
Vitamins, Fat Soluble, 94

Vitamins A, D, E, K
 Absorption dependent on ileum and
pancreas
 Accumulate in body fat, more potential for
toxicity
 Fat malabsorption conditions may cause
deficiency
○ Cystic fibrosis, celiac sprue, mineral oil intake
Vitamins, Fat Soluble, 94

Vitamin A (Retinol)
 Found: liver, leafy vegetables
 Functions: antioxidant, constituent of retinal




visual pigment
Deficiency: night blindness, dry skin
Excess: head ache, arthralgias, fatigue, skin
changes, sore throat, alopecia
Teratogenic: cleft palate, cardiac problems
Remember bear hunter who eats liver!
Vitamins, Fat Soluble, 97

Vitamin D
 Found: Fortified milk
 Function: Increases intestinal absorption of
calcium and phosphate, bone resorption
 Deficiency: Rickets (children), osteomalacia
(adults), hypocalcemic tetany
 Excess: Hypercalcemia, hypercalciuria, loss
of appetite, stupor. (Seen in sarcoidosis)
Vitamins, Fat Soluble, 97

Vitamin D, continued
 D2
○ Found in plants, pharmacological form
 D3
○ Found in milk, formed in sun exposed skin
 25-OH D3
○ Storage form
 1,25-(OH)2D3 (Calcitriol)
○ Active form
Vitamins, Fat Soluble, 97

Vitamin E
 Found: Vegetable oils, nuts, leafy
vegetables
 Function: Antioxidant, protects RBC’s and
membranes from free radical damage
 Deficiency: Increased fragility of RBC’s,
muscle weakness, neurodysfunction
Vitamins, Fat Soluble, 98

Vitamin K
 Found: Leafy vegetables, some fruits
 Function: Necessary for synthesis of
clotting factors II, VII, IX, X, protein C and S,
catalyzes γ-carboxylation of glutamic acid
residues
 Deficiency: Hemorrhage with increased PT,
PTT, normal bleeding time.
○ Neonatal hemorrhage, give Vitamin K at birth
○ Warfarin antagonizes Vitamin K
Vitamins, Water Soluble, 94
Vitamins B1 (thiamine), B2 (riboflavin), B3
(niacin), B5 (pantothenic acid), B6
pyridoxine, B12 (cobalamin), C (ascorbic
acid, biotin, folate
 All except B12 and folate wash out from
body, low risk of toxicity

Vitamins, Water Soluble, 94

Vitamin B1 (thiamine)
 Function: Component of thiamine
pyrophosphate, cofactor in:
○ Pyruvate dehydrogenase (glycolysis)
○ α-ketoglutarate dehydrogenase (TCA cycle)
○ Transketolase (HMP shunt)
○ Branched chain amino acid dehydrogenase
Vitamins, Water Soluble, 95

Vitamin B1 (thiamine), continued
 Deficiency:
○ Wernike-Korsakoff syndrome
 Seen in malnutrition, alcoholism
 Confusion, ophthalmoplegia, confabulation
○ Beriberi (dry)
 Polyneuritis, symmetrical muscle wasting
○ Beriberi (wet)
 High-output cardiac failure (dilated cardiomyopathy)
edema
Vitamins, Water Soluble, 95

Vitamin B2 (riboflavin)
 Function: Cofactor in oxidation and
reduction (FAD, FMN) B2=2 ATP
 Deficiency: Cheilosis, corneal
vascularization
Vitamins, Water Soluble, 95

Vitamin B3 (niacin)
 Function: Constituent of NAD, NADP, used in
redox reactions, B3=3 ATP
 Derived from tryptophan, requires B6 for
synthesis
 Deficiency: Pellagra (diarrhea, dermatitis,
dementia), glossitis
○ Hartnup disease (decreased tryptophan
absorption)
○ Malignant carcinoid syndrome (increased
tryptophan metabolism
○ INH (anti-TB) (decreased B6)
Vitamins, Water Soluble, 95

Vitamin B3 (niacin), continued
 Clinical use: Treatment of hyperlipidemia
(decrease LDL, increase HDL)
 Excess: Facial flushing, treat with aspirin
Vitamins, Water Soluble, 95

Vitamin B5 (pantothenate)
 Function: Component of CoA (cofactor in
acyl transfers) and fatty acid synthase
 Deficiency: Dermatitis, enteritis, alopecia,
adrenal insufficiency
Vitamins, Water Soluble, 95

Vitamin B6 (pyridoxine)
 Function: Converted to pyridoxal,
phosphate, cofactor in transamination
(ALT/AST), decarboxylation reactions,
glycogen phosphorylase, heme synthesis
 Required for synthesis of B3 (niacin)
 Deficiency: Convulsions, hyperirritability,
peripheral neuropathy
○ May be induced by INH, OCP’s
Vitamins, Water Soluble, 96

Vitamin B12 (cobalamin)
 Found: Only in animal products, synthesized
by microorganisms (large reserves in liver)
 Function: Cofactor for homocysteine
methyltransferase (transfers CH3 groups)
and methylmalonyl-CoA mutase
Vitamins, Water Soluble, 96

Vitamin B12 (cobalamin)
 Deficiency:
○ Macrocytic-megaloblastic anemia
○ Neurological symptoms
 Irreversible if prolonged
 Paresthesias
 Sub acute combined degeneration
- Posterior and lateral spinal columns
Vitamins, Water Soluble, 96

Vitamin B12 (cobalamin)
 Causes of deficiency
○ Intestinal malabsorption
 Sprue, enteritis, fish tapeworm
○ Lack of intrinsic factor
 Pernicious anemia
○ Absence of terminal ileum
 Crohn’s disease, surgical
 Schilling test to detect etiology of deficiency
Vitamins, Water Soluble, 96

Folic Acid
 Function: Converted to tetrahydrofolate
(THF), coenzyme used in 1-carbon
transfer/methylation reaction. Used in
synthesis of nitrogenous bases in DNA/RNA
 Deficiency:
○ Macrocytic-megaloblastic anemia
 Without neurological symptoms
○ Neural tube defects
 Prevent with prenatal supplements
Vitamins, Water Soluble, 96

Folic acid, continued
 Deficiency
○ Much smaller liver stores than B12
○ Most common US vitamin deficiency
 Especially in pregnancy, alcoholism
○ Can be caused by phenytoin, sulfonamides,
methotrexate
Vitamins, Water Soluble, 97

Biotin
 Function: Cofactor for carboxylation
enzymes, pyruvate carboxylase, acetyl-CoA
carboxylase, propionyl-CoA carboxylase
 Avidin (raw egg whites) binds biotin and
prevents absorption
 Deficiency: Dermatitis, alopecia, enteritis.
○ Antibiotic use or excessive raw eggs
Vitamins, Water Soluble, 97

Vitamin C (ascorbic acid)
 Found: Fruits, vegetables
 Function: Antioxidant, also:
○ Facilitates iron absorption by keeping Fe in
more absorbable Fe2+
○ Necessary for hydroxylation of proline and
lysine in collagen synthesis
○ Necessary for dopamine β-hydroxylase
(converts dopamine to norepinephrine)
Vitamins, Water Soluble, 97

Vitamin C (ascorbic acid)
 Deficiency: Scurvy
○ Swollen gums, bruising, anemia, poor wound
healing
Minerals, 98

Zinc
 Function: Involved in activity of 100+
enzymes. Important in zinc finger
(transcription factor motif)
 Deficiency: Delayed wound healing,
hypogonadism, decreased adult hair,
predisposes to alcoholic cirrhosis
Malnutrition, 98

Kwashiorkor
 Protein deficiency
 Skin lesions, liver malfunction (fatty change),
edema, anemia
Malnutrition, 98

Marasmus
 Total calorie deficiency
 Tissue and muscle wasting, loss of
subcutaneous fat, edema
Ethanol Metabolism, 98
Alcohol dehydrogenase operates via zero-order
kinetics
 NAD+ is limiting reagent
 Fomepizole inhibits alcohol dehydrogenase
 Disulfiram inhibits acetaldehyde dehydrogenase

Universal Electron Acceptors, 101

NAD+, NADP+
 Require Vitamin B3 (niacin) for production
 NAD+
○ Catabolic processes, carry reducing equivalents
as NADH
 NADP+
○ Anabolic processes, supply reducing equivalents
as NADPH
○ NADPH also used in respiratory burst, P-450

FAD+
 Requires Vitamin B2 (riboflavin) for production
Metabolism, 101

ATP Production (Glycolysis)
 Hydrolysis drives energetically unfavorable
reactions
 Aerobic metabolism
○ Produces 32 (heart/liver) 30 (muscle) ATP per
glucose
 Anaerobic metabolism
○ Produces 2 ATP per glucose
Hexokinase Vs. Glucokinase, 101
First step of glycolysis is glucose to G6P
 Reaction catalyzed by hexokinase or
glucokinase, 1st regulation point
 Hexokinase

 Ubiquitous, high affinity (low Km), low capacity
(low Vmax), feedback inhibited by product

Glucokinase
 Liver and pancreas β-cells, low affinity (high Km)
and high capacity (high Vmax) induced by
insulin, sequesters excess glucose in liver.
Hexokinase Vs. Glucokinase, 101
Glycolytic Enzyme Deficiency,
103
Deficiency of pyruvate kinase or
phosphoglucose isomerase
 Inability to maintain Na+-K+ ATPase
 RBC swelling, lysis
 Hemolytic anemia

 RBC’s depend solely on glycolysis of
glucose for metabolism
Pyruvate dehydrogenase
Deficiency, 103
Back up of substrate (pyruvate, alanine),
leads to lactic acidosis
 Congenital and acquired (B1 deficiency)
forms
 Neurologic deficits
 Treat by increasing intake of ketogenic
nutrients (high fat, lysine, leucine)

Pyruvate Metabolism, 103
Alanine carries AA to
liver from muscle
Oxaloacetate used to
in TCA cycle or gluconeogenesis
Transition from glycolysis to TCA cycle
End of anaerobic
glycolysis
Cori Cycle, 103
Muscle and RBC’s generate lactate via
anaerobic glycolysis
 Lactate sent to liver to be used in
gluconeogenesis
 Glucose can then be sent back and used
by muscle and RBC’s
 Loss of 4 ATP/Cycle

HMP Shunt, 105
Produces NADPH for fatty acid and steroid synthesis, and
glutathione reduction in RBC’s
Oxidative (irreversible)
and non-oxidative
(reversible) phases
Occurs in lactating
mammary glands, liver,
adrenal cortex, RBC’s
Respiratory Burst, 105



Produces reactive oxygen (HOCl) species for
immune response
Occurs in neutrophils, macrophages
Involves membrane-bound NADPH oxidase
(deficient in chronic
granulomatous disease)
Glucose-6-Phosphate
Dehydrogenase Deficiency, 106
G6PD produces NADPH, necessary to
keep glutathione reduced, which detoxifies
free radicals/peroxides
 Decreased NADPH leads to hemolytic
anemia due to damage from oxidizing
agents
 X-linked recessive,
most common
enzyme deficiency

Glucose-6-Phosphate
Dehydrogenase Deficiency, 106
Oxidizing agents include fava beans,
sulfanamides, primaquine, anti-TB drugs
 Affected individuals have malarial
resistance
 Heinz bodies

 Altered precipitated hemoglobin in RBC’s

Bite Cells
 From phagocytic removal of Heinz bodies by
spleen
Glucose-6-Phoshate
Dehydrogenase Deficiency, 106

Heinz bodies, bite cells
Disorders of Fructose
Metabolism, 106

Fructose intolerance
 Hereditary deficiency of aldolase B
 Autosomal recessive
 Fructose-1-phosphate accumulates, leading to
decrease in available phosphate, inhibits
glycogenolysis and gluconeogenesis
 Hypoglycemia, jaundice, cirrhosis,
vomiting
 Decrease intake of fructose and
sucrose
Disorders of Fructose
Metabolism, 106

Essential fructosuria
 Defect in fructokinase
 Autosomal recessive
 Benign, asymptomatic
 Fructose in blood and urine
Disorders of Galactose
Metabolism, 107

Classic galactosemia
 Absence of galactose-1-phosphate
uridyltransferase.
 Autosomal recessive
 Toxic damage from galactitol
 Failure to
thrive, jaundice,
hepatomegaly, infantile
cataracts, mental retardation
 Exclude galactose and lactose
from diet
Disorders of Galactose
Metabolism, 107

Galactokinase deficiency
 Autosomal recessive
 Galactitol accumulates if galactose is present in
diet
 Galactose appears in blood
and urine, infantile cataracts,
failure to track objects, lack of
social smile
Lactase Deficiency, 107
Age dependent or hereditary lactose
intolerance due to loss of brush-border
enzyme
 Bloating, cramps, osmotic diarrhea
 Avoid dairy products, lactase
supplements

Transport of alanine and
glutamine, 108


Glucose in muscle is oxidized to pyruvate,
producing energy
Pyruvate is transaminated to alanine, travels to
liver, providing nitrogen for urea cycle, and carbon
for gluconeogenesis
Hyperammonemia, 108
Acquired (liver disease) or hereditary
(urea enzyme deficiencies)
 Results in excess NH4+, depletes αketoglutarate, inhibits TCA cycle
 Tremor, slurring speech, somnolence,
vomiting, cerebral edema, blurred vision
 Treat with benzoate, phenylbutyrate

Ornithine Transcarbamoylase
Defiency, 108
Most common urea cycle disorder
 X-linked recessive
 Interferes with elimination of ammonia
 May present in first days of life
 Excess carbamoyl phosphate converted
to orotic acid
 Orotic acid in blood and urine,
decreased BUN, hyperammonemia

Phenylketonuria, 109
Decreased phenylalanine hydroxylase
or tetrahydrobiopterin cofactor.
 Tyrosine can not be synthesized,
becomes essential
 Autosomal recessive
 Increased phenylalanine
leads to excess
phenylketones in urine.

Phenylketonuria, 109
Mental retardation, growth retardation,
seizures, fair skin, eczema, musty body
odor
 Treat by increased tyrosine and
decreased phenylalanine in diet
 Maternal PKU, (deficiency in pregnancy)
causes mental retardation, growth
retardation, microcephaly, heart defects

Alkaptonuria, 109
Congenital deficiency of homogentisic acid
oxidase in degradative pathway of tyrosine
 Autosomal recessive
 Dark connective tissue, pigmented sclera,
urine turns black on standing, arthralgias

Albinism, 109

Congenital defect in either:
 Tyrosinase
○ Inability to synthesize melanin from tyrosine
○ Autosomal recessive
 Tyrosine transporters
○ Variable inheritance,
locus heterogenity
○ Decreased availability of
tyrosine for melanin
synthesis
Albinism, 109
Can result from lack of migration of
neural crest cells.
 Increased risk of skin cancer

Homocystinuria, 100





Autosomal recessive
3 forms, all result in excess homocysteine
1. Cystathionine synthase deficiency
2. Decreased affinity of
cystathionine synthase for
pyridoxal phosphate (treat
with increased B6 in diet)
3. Homocysteine
methyltransferase deficiency
Homocystinuria, 110
Cystine becomes essential
 Increased homocysteine in urine, mental
retardation, osteoporosis, tall stature,
kyphosis, lens subluxation,
atherosclerosis (MI and stroke)

Cystinuria, 110
Hereditary defect of renal tubular amino
acid transporter for cysteine, ornithine,
lysine, arginine in proximal convoluted
tubule.
 Excess cystine in precipitates, forms
cystine kidney stones.
 Autosomal recessive
 Treat with acetazolamide to
alkalinize urine.

Maple Syrup Disease, 110
Blocked degradation of branched amino
acids (Ile, Leu, Val), due to decreased αketoacid dehydrogenase.
 Results in accumulation of α-ketoacids
in blood
 Severe CNS defects, mental retardation,
death.
 Urine smells like maple syrup

Adenosine Deaminase
Deficiency, 111
Excess ATP and dATP imbalances
nucleotide pool (feedback inhibition of
ribonucleotide reductase)
 Prevents DNA synthesis
 Decreased lymphocyte count
 Major cause of severe combined
immunodeficiency disorder

Lesch-Nyhan Syndrome, 111
Absence of HGPRT leads to defective
purine salvage pathway
 Excess uric acid production
 X-linked recessive


Mental retardation, self-mutilation,
aggression, hyperuricemia, gout,
choreoathetosis
Orotic aciduria, 111

Inability to convert orotic acid UMP in de
novo pyrimidine synthesis pathway
 Defect in orotic acid
phosphoribosetransferase or orotidine 5’phosphate decarboxylase
Autosomal recessive
 Increased orotic acid in urine,
megaloblastic anemia, failure to thrive
 Treat with oral uridine

Insulin, 112
Synthesized in pancreas β cells
 Released in response to ATP from
glucose metabolism (depolarizing K+
channels)
 Anabolic effects:

 Increases glucose transport, glycogen
synthesis and storage, triglyceride synthesis
and storage, protein synthesis
 Increased Na+ retention, cellular K+ uptake
Insulin, 112
Inhibits glucagon release by pancreas α
cells
 Insulin dephosphorylates
 Serum C-peptide only present with
endogenous protein

 Lack of C-peptide indicated exogenous
insulin use
Insulin, 112
Insulin moves glucose into cells
 Some cells do not need insulin, use a
glucose transporter

 GLUT1: RBC’s, brain
 GLUT2: β islet cells, liver, kidney
 GLUT4: (insulin sensitive) adipose tissue,
skeletal muscle
Glycogen, 112
Branches: α (1,6) bonds
 Linkages: α (1,4) bonds
 Glycogen phosphorylates
 Skeletal muscle

 Glycogen undergoes glycogenolysis to form
glucose, which is metabolized during exercise

Hepatocytes
 Glycogen is stored and undergoes
glycogenolysis to maintain blood glucose levels
Glycogen Storage Disease, 113
All cause abnormal glycogen metabolism and accumulation
within cells
Disease
Findings
Deficient enzyme
Von Gierke’s (I)
Severe fasting
hypoglycemia,
increased glycogen in
liver, increased blood
lactate, hepatomegaly
Glucose-6-phosphate
Pompe’s (II)
Cardiomegaly
Lysosomal α-1,4
glucosidase (acid
maltase)
Cori’s (III)
Milder type I, normal
blood lactate levels
Debranching enzyme
McArdle’s (V)
Increased glycogen in Skeletal muscle
muscle, muscle
glycogen
cramps, myoglobinuria phosphorylase
Ketone Bodies, 115
In liver, fatty acids and amino acids are
metobolized to acetoacetate and βhydroxybutyrate for use in muscle and
brain
 Produced in response to starvation,
alcoholism
 Breath smells like acetone

Metabolic Fuel Use, 116

Exercise
 1st (seconds) Stored ATP, creatine
phosphate, anaerobic glycolysis
 2nd (minutes) +Oxidative phosphorylation
 3rd (hours) Glycogen and FFA oxidation,
glucose conserved
Metabolic Fuel Use, 116

Fasting and starvation
 Preserve glucose for brain and RBC’s
 Days 1-3
○ Hepatic glycogenolysis and glucose release
○ Adipose release of free fatty acids, used by
muscle and liver (in place of glucose)
○ Hepatic gluconeogenesis from peripheral
lactate and alanine, adipose tissue
Metabolic Fuel Use, 116

Fasting and starvation
 After 3 days
○ Muscle protein used for hepatic formation of
ketone bodies for brain and heart
 Several days
○ Ketone bodies become main energy source
for brain
○ Survival time determined by fat stores
Lipid Transport Enzymes, 117

Pancreatic lipase
 Degradation of dietary lipase in small
intestine

Lipoprotein lipase
 Degradation of TG in chylomicrons and
VLDL

Hepatic TG lipase
 Degradation of TG in IDL

Hormone sensitive lipase
 Degradation of TG in adipocytes
Cholesterol Synthesis, 116

Rate limiting step catalyzed by HMG-CoA
reductase
 Enzyme inhibited by statins


2/3 plasma cholesterol is esterified by lecithincholesterol
acyltransferase (LCAT)
Cholesterol ester transport
protein (CETP) mediates
transfer of cholesterol esters to
lipoprotein particles
Essential Fatty Acids, 116
Can not be synthesized, must be in diet
 Linoleic and linolenic acids
 Arachidonic acid, if linoleic acid is
absent
 Necessary for synthesis of eicosandoids

Lipoprotein Functions, 118
Lipoproteins are composed of varying
proportions of cholesterol, triglycerides,
phospholipids
 LDL transports cholesterol from liver to
tissues
 HDL transports cholesterol from tissues
to liver

Lipoprotein Functions, 118

Chylomicron
 Delivers dietary TG’s to tissue
 Delivers cholesterol to liver as chylomicron
remnants (depleted of triacylglycerols)
 Secreted by intestinal epithelial cells
 B-48, A-IV, C-II, E
 Familial dyslipidemia I
○ Increased chylomicrons
○ Elevated TG, cholesterol
○ Lipoprotein lipase deficiency or altered
apolipoprotein C-II
Lipoprotein, 118

VLDL
 Delivers hepatic TG’s to tissue
 Secreted by liver
 B-100, C-II, E
 Hypertriglyceridemia
○ Increased VLDL
○ Elevated TG
○ Hepatic overproduction of VLDL

IDL
 Formed by degradation of VLDL
 Delivers TG’s and cholesterol to liver, degraded to LDL’s
 B-100, E
Lipoprotein Functions, 118

LDL
 Delivers hepatic cholesterol to tissues
 Formed by lipoprotein lipase modification of
VLDL in tissue
 Taken up by target cells via receptor-mediated
endocytosis
 B-100
 Familial dyslipidemia IIa
○ Increased LDL
○ Elevated cholesterol
○ Autosomal dominant, absent/decreased LDL
receptor
Lipoprotein Functions, 118

HDL
 Mediates reverse cholesterol transport from
tissues to liver.
 Repository of apoC and apoE
 Secreted from liver and intestine
Abetalipoproteinemia, 118
Hereditary inability to synthesize
lipoproteins, because of deficiency in
apoB-100 and apoB-48
 Autosomal recessive, appears early in life
 Failure to thrive,
steatorrhea,
acanthocytosis, ataxia,
night blindness
