Fa: Biochemistry - Metabolism - 4

Front 1

How are NAD+ / NADP+ synthesized?

Back 1

Tryptophan (B6) → Niacin → NAD+ / NADP+

Front 2

How is Serotonin synthesized?

Back 2

Tryptophan (BH4, B6) → Serotonin

Front 3

How is Melatonin synthesized?

Back 3

Tryptophan (BH4, B6) → Serotonin → Melatonin

Front 4

How is Histamine synthesized?

Back 4

Histidine (B6) → Histamine

Front 5

How is Heme synthesized?

Back 5

Glycine (B6) → Porphyrin → Heme

Front 6

How is GABA synthesized?

Back 6

Glutamate (B6) → GABA

Front 7

How is Glutathione synthesized?

Back 7

Glutamate → Glutathione

Front 8

How is Creatinine synthesized?

Back 8

Arginine → Creatinine

Front 9

How is Urea synthesized?

Back 9

Arginine → Urea

Front 10

How is Nitric Oxide synthesized?

Back 10

Arginine (BH4) → Nitric Oxide

Front 11

Which disorder is caused by a deficiency of Phenylalanine Hydroxylase or ↓ BH4 (tetrahydrobiopterin cofactor)?

Back 11

Phenylketonuria

Front 12

What is the cause of Phenylketonuria?

Back 12

Autosomal recessive:
- Deficiency of Phyenylalanine Hydroxylase OR
- Decreased BH4 (tetrahydrobiopterin) cofactor = Malignant PKU
* Tyrosine becomes essential

Front 13

What are the symptoms of Phenylketonuria?

Back 13

- Increased phenylalanine leads to excess phenylketones (phenylacetate, phenyllactate, and phenylpyruvate) in urine
- Intellectual disability
- Growth retardation
- Seizures
- Fair skin
- Eczema
- Musty body odor (disorder or "AROMATIC" AA metabolism)

Front 14

How do you diagnose Phenylketonuria?

Back 14

Screened for 2-3 days after birth (normal at birth because of maternal enzyme during fetal life)

Front 15

How do you treat Phenylketonuria?

Back 15

- Decrease phenylalanine and increase tyrosine in diet
- Avoid artificial sweetener aspartame because it contains lots of phenyalanine

Front 16

What are the characteristics of Maternal Phenylketonuria (PKU)?

Back 16

- Lack of proper dietary therapy during pregnancy, if mom has PKU, the high levels of phenylalanine can buildup and affect fetus
- Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects

Front 17

Which disorder is caused by a deficiency of Homogentisate Oxidase?

Back 17

Alkaptonuria (Ochronosis)

Front 18

What is the cause of Alkaptonuria?

Back 18

Congenital deficiency of homogentisate oxidase in degradative pathway of tyrosine to fumarate
- Autosomal recessive
- Benign disease

Front 19

What are the findings of Alkaptonuria?

Back 19

- Dark CT
- Brown pigmented sclerae
- Urine turns black on prolonged exposure to air
- May have debilitating arthralgias (homogentisic acid is toxic to cartilage)

Front 20

What disease causes intellectual disability, growth retardation, seizures, fair skin, eczema, and MUSTY BODY ODOR?

Back 20

Phenylketonuria - caused by autosomal recessive deficiency of phenylalanine hydroxylase or decreased BH4 cofactor

Front 21

What disease causes dark CT, brown pigmented sclerae, and urine that turns black on prolonged exposure to air?

Back 21

Alkaptonuria - caused by congenital (autosomal recessive) deficiency of Homogentisate Oxidase

Front 22

What can cause Homocystinuria?

Back 22

- Cystathionine synthase deficiency
- Decreased affinity of cystathionine synthase for pyridoxal phosphate (PLP)
- Homocysteine methyltransferase deficiency

Front 23

What are the implications of cystathionine synthase deficiency, decreased affinity of cystathionine synthease for PLP, or homocysteine methyltransferase deficiency?

Back 23

Homocystinuria:
- All forms result in excess homocysteine
- ↑↑ homocysteine in urine
- Intellectual disability
- Osteoporosis
- Tall stature
- Kyphosis (curvature of spine)
- Lens subluxation (downward and inward)
- Thrombosis
- Atherosclerosis (stroke and MI)

Front 24

Which disorder is caused by a deficiency of tyrosinase?

Back 24

Albinism (prevents conversion of DOPA to Melanin)

Front 25

What disorder is caused by a defect of the renal PCT and intestinal AA transporter for Cysteine, Ornithine, Lysine, and Arginine (COLA)?

Back 25

Cystinuria
Cystine is made of 2 cysteines connected by a disulfide bond

Front 26

What is the cause of Cystinuria?

Back 26

- Hereditary (autosomal recessive) defect of the renal PCT and intestinal AA transporter for Cysteine, Ornithine, Lysine, and Arginine (COLA)
- Excess cystine in urine can lead to precipitation of hexagonal cystine stones
- 1:7000 births

Front 27

How do you diagnose Cystinuria? Treat?

Back 27

- Diagnose: urinary cyanide-nitroprusside test diagnostic

Treatment:
- Urinary alkalinization (eg, potassium citrate, acetazolamide)
- Chelating agents which increase solubility of cystine stones
- Good hydration

Front 28

What disorder is caused by blocked degradation of branched AAs (Isoleucine, Leucine, Valine)? Enzymatic cause?

Back 28

Maple Syrup Urine Disease
- ↓ α-Ketoacid Dehydrogenase (B1)
- Causes ↑ α-Ketoacids in the blood, especially those of Leucine
- Autosomal recessive

Front 29

What is the cause of Maple Syrup Urine Disease? Implications?

Back 29

- Blocked degradation of branched AAs (Ile, Leu, Val) d/t ↓ α-Ketoacid Dehydrogenase (B1)
- Causes ↑ α-Ketoacids in the blood, especially those of Leucine

Symptoms:
- Urine smells like maple syrup / burnt sugar
- Severe CNS defects
- Intellectual disability
- Death

Front 30

Which amino acids are not degraded in Maple Syrup Urine Disease?

Back 30

Branched AAs:
- Isoleucine
- Leucine
- Valine

I Love Vermont Maple Syrup from maple trees (with branches)

Front 31

How do you treat Maple Syrup Urine Disease?

Back 31

- Restriction of Isoleucine, Leucine, and Valine in diet
- Thiamine supplementation

Front 32

How does glucagon affect glycogen regulation?

Back 32

1. Glucagon binds glucagon receptors in liver
2. Activates adenylate cyclase
3. ATP → cAMP
4. cAMP stimulates PKA
5a. Activates Glycogen Phosphorylase Kinase
6a. Activates Glycogen Phosphorylase
7a. Glycogen broken down into glucose

5b. PKA also inhibits Glycogen Synthase
6b. Glucose does not form glycogen

Front 33

How does epinephrine acting on β-receptors affect glycogen regulation?

Back 33

1. Epinephrine binds β-receptors in liver and muscle
2. Activates adenylate cyclase
3. ATP → cAMP
4. cAMP stimulates PKA
5a. Activates Glycogen Phosphorylase Kinase
6a. Activates Glycogen Phosphorylase
7a. Glycogen broken down into glucose

5b. PKA also inhibits Glycogen Synthase
6b. Glucose does not form glycogen

Front 34

How does epinephrine acting on α-receptors affect glycogen regulation?

Back 34

1. Epinephrine binds α-receptors in liver
2. Calcium released from ER
3. Directly and via calcium-calmodulin in muscle during contraction activates Glycogen Phosphorylase Kinase
4. Activates Glycogen Phosphorylase
5. Glycogen broken down into glucose

Front 35

How does insulin affect glycogen regulation?

Back 35

1. Insulin binds Tyrosine Kinase Dimer Receptor in liver and muscle
2a. Activates Glycogen Synthase
3a. Glucose formed into glycogen

2b. Activates Protein Phosphatase
3b. Inhibits Glycogen Phosphorylase
4b. Inhibits breakdown of glycogen into glucose

Front 36

What kind of bonds are in glycogen?

Back 36

- Branches have α-(1,6) bonds
- Linkages have α-(1,4) bonds

Front 37

What happens to glycogen in skeletal muscle?

Back 37

Glycogenolysis → glucose-1P → glucose-6P

Rapidly metabolized during exercise

Front 38

What happens to glycogen in hepatocytes?

Back 38

- Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels
- Glycogen phosphorylase cleaves glucose-1P residues off branched glycogen until four remain before a branch point
- Then 4α-D-glucanotransferase (debranching enzyme) moves 3 x glucose-1P's from the branch to the linkage
- α-1,6-glucosidase (debranching enzyme) cleaves off last glucose-1P on branch

Front 39

How is glycogen synthesized?

Back 39

Glucose → Glucose-6P → Glucose-1P

Glucose-1P → UDP-Glucose via UDP-Glucose Pyrophosphorylaes

UDP-Glucose → Glycogen via Glycogen Synthase

Glycogen can add branches via Branching Enzyme

Front 40

How is glycogen metabolized?

Back 40

4. Glycogen → Limit Dextrin via Glycogen Phosphorylase (by removing glucose-1P residues until 4 glucose residues on branch remain)

5. 4-α-D-glucanotransferase (debranching enzyme) moves 3 glucose-1Ps from branch to linkage

6. α-1,6-glucosidase (debranching enzyme) cleaves off the last glucose-1P on the branch

- Then Glycogen Phosphorylase can continue removing glucose-1P residues

Front 41

A small amount of glycogen is degraded in lysosomes by what enzyme?

Back 41

α-1,4-glucosidase (acid maltase)

Front 42

What are the glycogen storage diseases? General characteristics?

Back 42

*Very Poor Carbohydrate Metabolism*
- Von Gierke disease (type 1)
- Pompe disease (type 2)
- Cori disease (type 3)
- McArdle disease (type 5)

All result in abnormal glycogen metabolism and an accumulation of glycogen within cells; all due to autosomal recessive deficiencies of enzymes

Front 43

What is the cause of Von Gierke disease (type 1 glycogen storage disease)? Findings? Treatment?

Back 43

Cause:
- Glucose-6-Phosphatase deficiency (autosomal recessive)

Findings:
- Severe fasting hypoglycemia
- ↑↑ glycogen in liver
- ↑ blood lactate
- Hepatomegaly

Treatment:
- Frequent oral glucose / cornstarch
- Avoidance of fructose and galactose

Front 44

What is the cause of Pompe disease (type 2 glycogen storage disease)? Findings? Other?

Back 44

Cause:
- Lysosomal α-1,4-glucosidase (acid maltase)
- Autosomal recessive

Findings:
- Cardiomyopathy
- Systemic findings leading to early death

Comments:
- Pompe trashes the Pump (heart, liver, and muscles)

Front 45

What is the cause of Cori disease (type 3 glycogen storage disease)? Findings? Other?

Back 45

Cause:
- Debranching enzyme (α-1,6-glucosidase) deficiency
- Autosomal recessive

Findings:
- Milder form of type 1 (Von Gierke)
- Normal blood lactate levels

Comments:
- Gluconeogenesis is intact

Front 46

What is the cause of McArdle disease (type V glycogen storage disease)? Findings? Other?

Back 46

Cause:
- Skeletal muscle glycogen phosphorylase (myophosphorylase) deficiency
- Autosomal recessive

Findings:
- ↑ glycogen in muscle, but can't break it down
- Leads to painful muscle cramps, myoglobinuria (red urine) w/ strenuous exercise, and arrhythmia from electrolyte abnormalities

Comments:
- McArdle = Muscle

Front 47

Which disease presents with severe fasting hypoglycemia, ↑↑ glycogen in liver, ↑ blood lactate, and hepatomegaly? Cause?

Back 47

Von Gierke Disease (type 1 Glycogen Storage Disease)
- Glucose-6-Phosphatase Deficiency
- Autosomal recessive
- Treatment: frequent oral glucose/cornstarch, avoid fructose and galactose

Front 48

Which disease presents with cardiomyopathy and systemic findings that lead to an early death? Cause?

Back 48

Pompe Disease (type 2 glycogen storage disease)
- Lysosomal α-1,4-glucosidase (acid maltase) deficiency
- Autosomal recessive
- Pompe trashes the Pump (heart, liver, and muscle)

Front 49

Which disease presents as a milder form of Von Gierke Disease with normal blood lactate levels? Cause?

Back 49

Cori Disease (type 3 glycogen storage disease)
- Debranching enzyme (α-1,6-glucosidase) deficiency
- Autosomal recessive
- Gluconeogenesis is still intact

Front 50

Which disease presents with painful muscle cramps, myoglobinuria (red urine) w/ strenuous exercise, and arrhythmia? Cause?

Back 50

McArdle Disease (type 5 glycogen storage disease)
- Skeletal muscle glycogen phosphorylase (myophosphorylase) deficiency
- Autosomal recessive
- ↑ Glycogen in muscle that can't be broken down causes the severe muscle cramps
- Arrhythmia caused by electrolyte abnormalities
- McArdle = Muscle

Front 51

What are the lysosomal storage diseases? General characteristics?

Back 51

Sphingolipidoses:
- Fabry Disease
- Gaucher Disease
- Niemann-Pick Disease
- Tay-Sachs Disease
- Krabbe Disease
- Metachromatic Leukodystrophy

Mucopolysaccharidoses:
- Hurler Syndrome
- Hunter Syndrome