Fa: Biochemistry - Metabolism - 3

Front 1

What are the disorders of Galactose Metabolism?

Back 1

- Galactokinase deficiency
- Classic galactosemia

Front 2

What happens in Galactokinase Deficiency? Cause?

Back 2

- Hereditary deficiency of Galactokinase
- Autosomal recessive

- Galacitol accumulates if galactose present in diet
- Relatively mild condition
- Galactose appears in blood and urine
- Infantile cataracts
- May initially present as failure to track objects or to develop a social smile

Front 3

What happens in Classic Galactosemia? Cause? Treat?

Back 3

- Absence of Galactose-1-Phosphate Uridyltransferase
- Autosomal Recessive

- Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in lens of eye)
- Symptoms: failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability
- May lead to E. coli sepsis in neonates

- Treatment: exclude galactose and lactose (galactose + glucose) from diet

Front 4

What is the difference in causes of Galactokinase Deficiency and Classic Galactosemia?

Back 4

- Galactokinase deficiency: deficiency of galactokinase, galactitol accumulates if galactose present in diet; autosomal recessive

- Classic galactosemia: absence of galactose-1P uridyltransferase, damage is caused by accumulation of toxic substances (galactitol - in lens of eye); depletion of PO4-; autosomal recessive

Front 5

What is the difference in symptoms of Galactokinase Deficiency and Classic Galactosemia?

Back 5

Galactokinase deficiency:
- Mild condition
- Galactose appears in blood and urine
- Infantile cataracts - may initially present as failure to track objects or to develop a social smile

Classic galactosemia:
- Failure to thrive
- Jaundice
- Hepatomegaly
- Infantile cataracts (accumulation of galactitol in lens)
- Intellectual disability
- Can lead to E. coli sepsis in neonates

Front 6

Which of the disorders of fructose deficiency is similar to one of the disorders of galactose deficiency?

Back 6

Fructose Intolerance (d/t deficiency of Aldolase B) is similar to Classic Galactosemia (d/t deficiency of Galactose-1P Uridyltransferase

*FAB-GUT*
Fructose is to Aldolase B as Galactose is to Uridyl-Transferase

Front 7

What is an alternative method of trapping glucose in the cell?

Back 7

Convert it to its alcohol counterpart, called Sorbitol, via Aldose Reductase

Front 8

How is sorbitol synthesized? What can happen to it next?

Back 8

1. Glucose → Sorbitol (via Aldose Reductase and NADPH)

2. Sorbitol → Fructose (via Sorbitol Dehydrogenase and NAD+)

2nd reaction only occurs in certain tissues (liver, ovaries, seminal vesicles)

Front 9

What are the implications if tissues don't have both enzymes to generate sorbitol and to dehydrogenate sorbitol?

Back 9

- Tissues like Schwann cells, retina, the lens, and kidneys only have Aldose Reductase to generate Sorbitol
- These tissues are at risk for intracellular sorbitol accumulation, causing osmotic damage (eg, cataracts, retinopathy, and peripheral neuropathy with chronic hyperglycemia in diabetes)

Front 10

What causes cataracts, retinopathy, and peripheral neuropathy in patients with chronic hyperglycemia / diabetes?

Back 10

- Glucose is converted to Sorbitol via Aldose Reductase
- Schwann cells (→ peripheral neuropathy), retina (→ retinopathy), lens (→ cataracts), and kidneys don't have sufficient Sorbitol Dehydrogenase to remove Sorbitol, leading to OSMOTIC DAMAGE

Front 11

Besides glucose, high levels of what other molecule can also be converted by Aldose Reductase? Product?

Back 11

Galactose → Galactitol (via Aldose Reductase)

Front 12

What causes Lactose Intolerance?

Back 12

- Insufficient lactase enzyme → dietary lactose intolerance
- Lactase functions on the brush border to digest lactose (in human and cow milk) into glucose and galactose

Front 13

What are the two types of lactase deficiency? How do they differ?

Back 13

Primary:
- Age dependent decline after childhood (Absence of lactase-persistent allele)
- Common in Asian, African, or Native American heritage

Secondary:
- Loss of brush border d/t gastroenteritis (eg, rotavirus), autoimmune disease, etc

Front 14

What are the signs / symptoms of Lactose Intolerance?

Back 14

- Stool demonstrates ↓ pH
- Breath shows ↑ H+ content with lactose tolerance test
- Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance

- Bloating, cramps, flatulence, osmotic diarrhea

Front 15

How do you treat Lactose Intolerance?

Back 15

Avoid dairy products or add lactase pills to diet

Front 16

What form of amino acids are found in proteins in humans?

Back 16

Only L-form of amino acids

Front 17

What type of amino acids need to be supplied in the diet?

Back 17

Essential Amino Acids:
- Glucogenic: Met, Val, His
- Glucogenic / Ketogenic: Ile, Phe, Thr, Trp
- Ketogenic: Leu, Lys

Front 18

What are the glucogenic essential amino acids?

Back 18

- Methionine (Met)
- Valine (Val)
- Histidine (His)

Front 19

What are the glucogenic / ketogenic essential amino acids?

Back 19

- Isoleucine (Ile)
- Phenylalanine (Phe)
- Threonine (Thr)
- Tryptophan (Trp)

Front 20

What are the ketogenic essential amino acids?

Back 20

- Leucine (Leu)
- Lysine (Lys)

Front 21

What are the acidic amino acids?

Back 21

- Aspartic Acid (Asp)
- Glutamic Acid (Glu)

Negatively charged at body pH

Front 22

What are the basic amino acids?

Back 22

- Arginine (Arg) - most basic
- Lysine (Lys)
- Histidine (His) - no charge at body pH

Front 23

Which amino acids are required during periods of growth?

Back 23

- Arginine (Arg) - most basic AA
- Histidine (His) - basic, but no charge at body pH

Front 24

Which amino acids are increased in histones? Function?

Back 24

- Arginine (Arg) - most basic AA
- Lysine (Lys) - basic

They bind negatively charged DNA

Front 25

What process is necessary for amino acid catabolism?

Back 25

Urea Cycle

Front 26

What is the function of the Urea Cycle?

Back 26

- AA catabolism results in the formation of common metabolites (eg, pyruvates, acetyl-CoA)
- These serve as metabolite fuels
- Excess nitrogen (NH3) generated by this process is converted to urea and excreted by the kidneys

Front 27

How do you remember the intermediates in the Urea Cycle?

Back 27

Ordinarily, Careless Crappers Are Also Frivolous About Urination:

- Ornithine + Carbomoyl phosphate →
- Citrulline + Aspartate →
- Argininosuccinate →
- Arginine → (+Fumarate)
- Urea→

Front 28

What are the enzymes in the Urea Cycle?

Back 28

1. Ornithine Transcarbamylase
2. Argininosuccinate Synthetase
3. Argininosuccinase
4. Arginase

Front 29

What is Urea made of?

Back 29

- NH3 (ammonia)
- CO2
- Aspartate (donates NH2)

Front 30

How is Carbamoyl Phosphate synthesized for the Urea Cycle?

Back 30

In mitochondria, Carbamoyl Phosphate Synhtetase I combines CO2 + NH3

Uses 2 ATP and requires N-acetylglutamate as a cofactor

Front 31

What happens to Carbamoyl Phosphate in Urea Cycle?

Back 31

Combines with Ornithine via Ornithine Transcarbamylase → Citrulline

Front 32

What happens to Citrulline in Urea Cycle?

Back 32

Citrulline combines with Aspartate via Argininosuccinate Synthetase → Argininosuccinate

Requires one ATP → AMP + PPi

Front 33

What happens to Argininosuccinate in Urea Cycle?

Back 33

Argininosuccinase breaks it down into Fumarate (released) and Arginine (continues in Urea Cycle)

Front 34

What happens to Arginine in Urea Cycle?

Back 34

Arginase combines Arginine with H2O to release Urea (which goes to kidney) and Ornithine (regenerated to continue Urea Cycle)

Front 35

What processes allow safe transport of ammonia in the body?

Back 35

Cori Cycle and Alanine Cycle

Front 36

How do amino acids (ammonia / NH3) get safely transported from the muscle to the liver (to be converted to urea)?

Back 36

Muscle:
- Amino Acids (NH3) + α-Ketoglutarate → Glutamate (NH3) + α-Ketoacids

- Glutamate (NH3) + Pyruvate → Alanine (NH3) + α-Ketoglutarate

Alanine Cycle:
- Alanine (NH3) transported to liver

Liver:
- Alanine (NH3) + α-Ketoglutarate → Glutamate (NH3) + Pyruvate

- Glutamate (NH3) →→ Urea (NH3) → kidney

Front 37

What is the Alanine Cycle?

Back 37

1. Alanine (NH3) transported from muscle to liver
2. Alanine (NH3) + α-Ketoglutarate → Glutamate (NH3) + Pyruvate
3. Pyruvate → Glucose
4. Glucose transported from liver back to muscle
5. Glucose → Pyruvate
6. Pyruvate + Glutamate (NH3) → Alanine (NH3) + α-Ketoglutarate

Front 38

What is the Cori Cycle?

Back 38

In muscle:
- Glucose → Pyruvate
- Pyruvate → Lactate

Cori Cycle:
- Lactate transported from muscle to liver

In liver:
- Lactate → Pyruvate
- Pyruvate → Glucose (overlaps with Alanine Cycle)

Cori / Alanine Cycle:
- Glucose transported from liver back to muscle

Front 39

What can cause Hyperammonemia?

Back 39

Acquired (eg, liver disease)

Hereditary (eg, urea cycle enzyme deficiency)
- N-acetylglutamate deficiency
- Ornithine transcarbamylase deficiency
- Etc.

Front 40

What does Hyperammonemia cause? Symptoms?

Back 40

- Excess NH4+ → depletes α-Ketoglutarate, leading to inhibition of TCA cycle

- Symptoms: tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision

Front 41

How do you treat Hyperammonemia?

Back 41

- Limit protein in diet

- Benzoate or phenylbutyrate (both of which bind AA and lead to excretion) can be given to ↓ ammonia levels)

- Lactulose can acidify the GI tract and trap NH4+ for excretion

Front 42

What are the implications of an N-acetylglutamate deficiency?

Back 42

- Required cofactor for Carbamoyl Phosphate Synthetase I
- Absence → Hyperammonemia (because Urea Cycle requires Carbamoyl Phosphate)

Front 43

What is the presentation of an N-acetylglutamate deficiency?

Back 43

Identical to Carbamoyl Phosphate Synthetase I deficiency:
- Hyperammonemia: tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
- ↑ Ornithine with normal urea cycle enzymes suggests hereditary N-acetylglutamate deficiency

Front 44

What is the most common urea cycle disorder? Cause?

Back 44

- Ornithine Transcarbamylase Deficiency (which is supposed to combine Carbamoyl Phosphate and Ornithine to make Citrulline)

- X-linked recessive

Front 45

What are the implications of an Ornithine Transcarbamylase Deficiency?

Back 45

- Interferes with the body's ability to eliminate ammonia
- Often evident in the first few days of life, but may present with late onset
- Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway)

Front 46

What are the lab findings of Ornithine Transcarbamylase Deficiency?

Back 46

- ↑ Orotic acid in blood and urine (made from excess unused Carbamoyl Phosphate)
- ↓ BUN
- Hyperammonemia
- No megaloblastic anemia (vs orotic aciduria)

Front 47

What are the amino acid derivatives of Phenylalanine?

Back 47

- Tyrosine → Thyroxine
- Melanin
- Dopamine → Norepinephrine → Epinephrine

Front 48

What are the amino acid derivatives of Tryptophan?

Back 48

- NAD+ / NADP+
- Serotonin → Melatonin

Front 49

What are the amino acid derivatives of Histidine?

Back 49

Histamine

Front 50

What are the amino acid derivatives of Glycine?

Back 50

Porphyrin → Heme

Front 51

What are the amino acid derivatives of Glutamate?

Back 51

- GABA
- Glutathione

Front 52

What are the amino acid derivatives of Arginine?

Back 52

- Creatine
- Urea
- Nitric Oxide

Front 53

How is Thyroxine (T4) synthesized?

Back 53

Phenyalanine (BH4) → Tyrosine → Thyroxine

Front 54

How is Melanin synthesized?

Back 54

Phenyalanine (BH4) → Tyrosine (BH4) → Dopa → Melanin

Phe → Tyr via Phenylalanine Hydroxylase
Tyr → DOPA via Tyrosine Hydroxylase
DOPA → Melanin via Tyrosinase

Front 55

How is Dopamine synthesized?

Back 55

Phenyalanine (BH4) → Tyrosine (BH4) → Dopa (Vitamin B6) → Dopamine

Phe → Tyr via Phenylalanine Hydroxylase
Tyr → DOPA via Tyrosine Hydroxylase
DOPA → Dopamine via DOPA Decarboxylase

Front 56

How is Norepinephrine synthesized?

Back 56

Phenyalanine (BH4) → Tyrosine (BH4) → Dopa (Vitamin B6) → Dopamine (Vitamin C) → Norepinephrine

Phe → Tyr via Phenylalanine Hydroxylase
Tyr → DOPA via Tyrosine Hydroxylase
DOPA → Dopamine via DOPA Decarboxylase
Dopamine → NE

Front 57

How is Epinephrine synthesized?

Back 57

Phenyalanine (BH4) → Tyrosine (BH4) → Dopa (Vitamin B6) → Dopamine (Vitamin C) → Norepinephrine (SAM) → Epinephrine

Phe → Tyr via Phenylalanine Hydroxylase
Tyr → DOPA via Tyrosine Hydroxylase
DOPA → Dopamine via DOPA Decarboxylase
Dopamine → NE requires Vitamin C
NE → Epinephrine requires SAM