Biochem

Front 1

Pyruvate dehydrogenase deficiency

Back 1

PDH usually converts pyruvate to acetyl-CoA to enter Krebs cycle. If no PDH, pyruvate will be converted to lactate via lactate dehydrogenase, causing lactic acidosis.

Findings: neuro defects, lactic acidosis, high serum alanine.

Lysine and Leucine are the only purely ketogenic AAs --> do not lead to lactic acidosis!

Front 2

Hexokinase

Back 2

Glucose to G6P

In most tissues, but NOT liver or pancreatic beta cells

Low Km (active at low concentrations of substrate; high affinity)

Low Vmax (decreased capacity)

No effect of insulin

Feedback inhibited by product! (G6P)

Gene mutation NOT associated w/MODY

Front 3

Glucokinase

Back 3

Glucose to G6P

ONLY in liver and pancreatic beta cells

High Km (active at high concentrations of substrate; low affinity)

High Vmax (increased capacity; no limit really)

Regulated by insulin

No feedback inhibition (active regardless of product levels)

Gene mutation associated w/MODY

Front 4

3 irreversible steps of glycolysis

Back 4

Glucokinase/hexokinase (glucose-->G6P)

Phosphofructokinase-1 (F6P-->F1,6bisphosphonate** main regulatory step!)

Pyruvate kinase (Phospoenolpyruvate-->pyruvate)

Front 5

4 irreversible of gluconeogenesis

Back 5

Pyruvate carboxylase (pyruvate-->oxaloacetate; in mito)

Phosphoenolpyruvate carboxylase (oxaloacetate-->phosphoenolpyruvate; in cytosol)

Fructose-1,6-bisphosphonate (F1,6BP-->F6P; in cytosol)

Glucose-6-phosphotase (G6P-->glucose; in ER)

Front 6

PKU

Back 6

Phenylalanine--(BH4 + phenylalanine hydoxylase)-->

Tyrosine--(BH4 + tyrosine hydroxylase)-->

Dopa--(VitB6)-->

Dopamine--(VitC)-->

NE--(SAM)-->

Epinephrine

- PKU due to decr phenylalanine hydroxylase or BH4 (malignant PKU, due to decr dihydropterin reductase).

- Tyrosine becomes essential (decr phenylalanine and incr tyrosine in diet)

- Phenylketones found in urine

- Intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor

Front 7

Gilbert Syndrome

Back 7

Hereditary hyperbilirubinemia

Mildly ↓ UDP glucuronosyltransferase activity and ↓ uptake of bilirubin by hepatocytes

Asymptomatic/mild jaundice

↑ unconjugated bilirubin

Front 8

Crigler-Najjar, type 1

Back 8

ABSENT UDP glucuronosyltransferase

Patients die w/in a few years - jaundice, kernicterus

↑ unconjugated bilirubin

Tx: plasmapheresis, phototherapy

Type 2 is less severe, responds to phenobarbital

Front 9

Dubin-Johnson Syndrome

Back 9

Defective liver excretion

↑ conjugated bilirubin

Grossly black liver, benign

Front 10

Rotor Syndrome

Back 10

Similar to Dubin-Johnson, but even milder

No black liver

Front 11

Irreversible reactions in glycolysis (catalysts)

Back 11

Hexokinase/glucokinase

Phosphofructokinase-1

Pyruvate kinase

Front 12

Irreversible reactions (catalysts)

Back 12

Pyruvate carboxylase

Phosphoenolpyruvate (PEP) carboxylase

Fructose-1,6-bisphosphonate

Glucose-6-phosphatase

Front 13

Pyruvate dehydrogenase

Back 13

Mitochondrial enzyme linking glycolysis and TCA cycle (irreversible)

Cofactors: TLC For Nancy (Thiamine, Lipoic Acid, Coenzyme A, FAD, NAD)

If deficiency = buildup of pyruvate, shunted to lactate and alanine

Sx: neuro defects, lactic acidosis, ↑ serum alanine

Rx: ↑ ketogenic nutrients (lysine and leucine = ketogenic!, fats)

Front 14

Electron transport inhibitors

Back 14

↓ proton gradient and block ATP synthesis

Rotenone, Cyanide, CO, antimycin A

Front 15

ATP synthase inhibitors

Back 15

Directly inhibit mito ATP synthase

↑ proton gradient

Oligomycin

Front 16

Uncoupling agents

Back 16

↑ permeability of membrane

↓ proton gradient, ↑ O2 consumption

ATP synthesis stops, but electron transport continues

HEAT

2,4-dinitrophenol (weight loss), aspirin (high doses), thermogenin in brown fat

Front 17

HMP shunt

Back 17

Source of NADPH

For reductive reactions (glutathione reductase in RBCs, FA and cholesterol biosynthesis, needed w/NADPH oxidase for neuts and monocytes)

Also to make ribose (nucleotide synthesis)

No ATP used/produced

Oxidative: Glucose-6-P-dehydrogenase (G6PD)

Nonoxidative: Phosphopentose isomerase, transketolases, requires B1 (thiamine) (Wernicke-Korsakoff disease: transketolase does not bind B1 well, WK syndrome, give extra thiamine)

Front 18

G6PD deficiency

Back 18

NADPH needed to keep glutathione reduced (reduced glutathione detoxifies free radicals and peroxides)

↓ NADPH in RBCs causes hemolytic anemia due to poor RBC defines vs. oxidizing agents and infection

Xr, common in blacks (malarial resistance)

Heinz bodies (oxidized Hb precipitated in RBCs)

Bite cells (due to splenic macros)

Front 19

Essential fructosuria

Back 19

Fructokinase deficiency

AR

Fructose in blood and urine

Benign, asymptomatic (fructose not trapped in cells)

Front 20

Fructose intolerance

Back 20

Aldolase B deficiency

AR

Fructose-1-P accumulates in cells, ↓ available phosphate (inhibits gycogenolysis and gluconeogenesis)

Sx after weening and when eat fruit, juice, honey

Urine dipstick NEG b/c only measures glucose

Sx: hypoglycemia, jaundice, cirrhosis, vomiting

Rx: ↓ intake of fructose and sucrose

Front 21

Disaccharide composition

Back 21

Maltose = Glucose + Glucose

Sucrose = Glucose + Fructose

Lactose = Glucose + Galactose

Front 22

Galactokinase deficiency

Back 22

Galactokinase deficiency, galactitol accumulates if galactose in diet

AR

Relatively mild

Sx: galactose in blood and urine, infantile cataracts

Front 23

Classic galactosemia

Back 23

Galactose-1-phosphate uridyltransferase

AR

G1P and galactitol build up

Sx: jaundice, hepatomegaly, infantile cataracts, intellectual disability

Rx: exclude galactose and lactose from diet

Front 24

Sorbitol

Back 24

Traps glucose in cell by converting to alcohol

Osmotic, so water rushes in.

Aldose reductase = glucose to sorbitol

Sorbitol dehydrogenase = sorbitol to fructose

Only (or mainly) aldose reductase: schwann cells, retina, kidneys, lens (primarily)

Front 25

Hyperammonemia

Back 25

Acquired or hereditary

Excess NH4+, depletes alpha-ketoglutarate, inhibition of TCA cycle

Rx: limit protein, benzoate or phenylbutyrate bind AA and lead to excretion (↓ ammonia levels), lactulose (acidifies GIT, traps NH4+ for excretion)

↓ BUN, ↑ ammonia in blood

Front 26

N-acetylglutamate deficiency

Back 26

Required cofactor for carbamoyl phosphate synthase I (CO2+NH3 to carbamoyl phosphate)

(Same presentation as carb-phos-synthase deficiency, but ↑ ornithine here)

↓ BUN, ↑ ammonia in blood

Front 27

Ornithine transcarbamylase deficiency

Back 27

Most common urea cycle disorder (carbamoyl phosphate to citrulline [leaves mito])

XR

Body can't eliminate ammonia

↓ BUN, ↑ ammonia in blood, ↑ orotic acid in blood

(XR = men more "orotic" than women)

Front 28

Amino acid derivatives (to epinephrine)

Back 28

Phenylalanine → tyrosine → dopa (to melanin) → Dopamine → NE → EPI

Front 29

Phenylketonuria

Back 29

↓ phenylalanine hydroxylase or ↓ BH4 (tetrahydrobiopterin cofactor)

Tyrosine becomes ESSENTIAL (b/c can't make from phenylalanine!)

AR

↑ phenylalanine = excess phenylketones in urine

Sx: intellectual disability, growth retardation, fair skin, eczema, musty body odour (aromatic aa)

Rx: ↓ phenylalanine, ↑ tyrosine in diet

Maternal PKU: lack of proper rx = microcephaly, intellectual disability, growth retardation, congenital heart defects

Front 30

Alkaptonuria (ochronosis)

Back 30

↓ homogentisate oxidase as tyrosine degraded to fumarate

AR, benign

DARK CT, brown sclera, black urine on prolonged exposure to air. May have debilitating arthralgia (homogentisic acid toxic to cartilage)

Front 31

Homocystinuria

Back 31

Methionine ← Homocystine → Cystathionine → Cystine

AR

1) Cystathionine synthase deficiency

2) ↓ affinity of cystathione synthase for pyridoxal phosphate (B6, pyridoxine)

3) Homocysteine methyltransferase (methionine synthase) deficiency

Sx: ↑↑↑ homocystine in urine, intellectual disability, osteoporosis, tall, kyphosis, lens subluxation, thrombus and atherosclerosis (MI early in life)

Front 32

Cystinuria

Back 32

Defect of renal PCT and intestinal aa transporter for cysteine, ornithine, lysine and arginine (COLA)

AR

Precipitation of hexagonal cystine stones

Rx: urinary alkalinization, chelating agents, good hydration

Front 33

Maple syrup urine disease

Back 33

Blocked degradation of branched amino acids

"I love Vermont" = isoleucine, leucine, valine

↓ alpha-ketoacid dehydrogenase (B1)

AR

Urine smells like maple syrup/burnt sugar

↑ alpha-ketoacids in blood (esp leucine)

Sx: severe CNS defects, intellectual disability, death

Rx: restriction of leucine, isoleucine and valine in diet, thiamine supplementation

Front 34

Alcohol metabolism

Back 34

Alcohol → acetylaldehyde → acetate

via alcohol dehydrogenase and acetaldehyde dehydrogenase

Acetylaldehyde responsible for hangovers

Decreased levels of acetaldehyde dehydrogenase in Asians, inhibited by disulfuram

Front 35

Von Gierke disease

Back 35

Glucose-6-phosphatase deficiency (reversal of hexokinase)

AR

Sx: SEVERE fasting hypoglycemia, ↑ glycogen in liver, ↑ blood lactate, hepatomegaly

Rx: frequent oral glucose/cornstarch, avoidance of fructose and galactose

Front 36

Pompe Disease

Back 36

Lysosomal alpha-1,4-glucosidase deficiency

AR

Sx: Cardiomyopathy, muscle weakness, early death

"Trashes the Pompe" (heart)

Front 37

Cori disease

Back 37

Debranching enzyme deficiency (alpha-1,6-glucosidase)

AR

Sx: milder form of type I, normal blood lactate

Front 38

McArdle Disease

Back 38

Skeletal muscle glycogen phosphorylase deficiency

AR

↑ glycogen in muscle, but can't b/d! cramps, myoglobulinuria (red urine) w/strenuous exercise, arrhythmia from electrolyte abnormalities

NO hepatomegaly

"McArdle can't do hurdles"

Front 39

Ketone bodies

Back 39

Acetoacetate, beta-hydroxybutyrate (and acetone, no energy)

Can make acetyl CoA to be used in TCA

Used by brain and muscle

Fruity odor to breath

Brain fuel use:

1/2-1 day = glycogen

up to day 5-7 = gluconeogenesis

1 week+ = ketone bodies (adipose tissue)

RBCs lack mitochondria and cannot use ketones!! (glycolysis only)

Front 40

Cholesterol synthesis

Back 40

Rate-limiting step catalyzed by HMG-CoA reductase (statins competitively and irreversibly inhibit)