Lecture 18: Amino Acid Metabolism

Question 1

In animals and humans, _____ and _____ recycle NH3 from the breakdown of nitrogenous compounds (originally consumed in the diet) for the synthesis of aa, proteins, and other nitrogenous compounds

Answer 1

In animals and humans, Glutamate Dehydrogenase** (**GDH)** and **Glutamine Synthase (GS) recycle NH3 from the breakdown of nitrogenous compounds (originally consumed in the diet) for the synthesis of aa, proteins, and other nitrogenous compounds

Question 2

AAs surplus to these needs are broken down (cannot be stored) C skeleton recycled or ________ for energy, amino group excreted as _________

• AA oxidation accounts for approx 10-15% of daily energy production
• can be increased in some disease states and in starvation

Answer 2

AAs surplus to these needs are broken down (cannot be stored) C skeleton recycled or oxidized** for energy, amino group excreted as **urea

• AA oxidation accounts for approx 10-15% of daily energy production
• can be increased in some disease states and in starvation

Question 3

____________________ (nitrogen excretion >> nitrogen consumption)

• protein breakdown ___ protein synthesis
• starvation
• cachexia (cancer, congestive heart failure, COPD et al)
• dietary deficiency of essential aa’s

__________________ (nitrogen consumption >> nitrogen excretion)

• protein synthesis ___ protein breakdown
• growing children
• pregnancy

Answer 3

Negative nitrogen balance (nitrogen excretion >> nitrogen consumption)

• protein breakdown > protein synthesis (loss of lean body mass -muscle)
• starvation
• cachexia (cancer, congestive heart failure, COPD et al)
• dietary deficiency of essential aa’s

Positive nitrogen balance (nitrogen consumption >> nitrogen excretion)

• protein synthesis > protein breakdown (accretion of lean body mass -muscle)
• growing children
• pregnancy

Question 4

Answer 4

Question 5

Essential and Non-Essential Amino Acids

Answer 5

Question 6

Answer 6

Question 7

Answer 7

Question 8

Answer 8

Question 9

Removal of amino group converts amino acid to _____________ (carbon skeleton of aa)

Common pairs:

• alanine/_________ (3C)
• aspartate/_________ (4C)
• glutamate/____________ (5C)

Answer 9

Removal of amino group converts amino acid to alpha-keto acid (carbon skeleton of aa)

Common pairs:

• alanine/pyruvate (3C)
• aspartate/oxaloacetate (4C)
• glutamate/alpha-ketoglutarate (5C)

Question 10

• __________ (aminotransferase) enzymes catalyze the transfer of an amino group from an amino acid to an alpha-keto acid.
• Amino donor becomes an alpha-keto acid while the amino acceptor becomes an aa
• All aminotransferases utilize ___________________________ as a cofactor

Answer 10

• Transaminase (aminotransferase) enzymes catalyze the transfer of an amino group from an amino acid to an alpha-keto acid.
• Amino donor becomes an alpha-keto acid while the amino acceptor becomes an aa
• All aminotransferases utilize PLP (pyridoxal phosphate, B group vitamin) as a cofactor

Question 11

The most common aa acceptors are ________ (forming glutamate) and ________ (forming aspartate)

Answer 11

The most common aa acceptors are a-ketoglutarate** (forming glutamate) and **oxaloacetate (forming aspartate)

Question 12

Tranamination reactions are an interface between AA metabolism and energy metabolism

• oxaloacetate and __________ are intermediates in the TCA cycle
• oxaloacatate and _________ are gluconeogenic precursors

Answer 12

Tranamination reactions are an interface between AA metabolism and energy metabolism

• oxaloacetate and a-ketoglutarate are intermediates in the TCA cycle
• oxaloacatate and pyruvate are gluconeogenic precursors

Question 13

Most transaminases have a preference for just two amino group acceptors. What are these acceptors and why?

Answer 13

Most transaminases have a preference for a-ketoglutarate** or **oxaloacetate as amino group acceptors.

• Amino groups of many different AAs end up in glutamate/aspartate
• More efficient to have one amino acid oxidase and channel all amino groups into glutamate than to dedicated one for each of the 20

Question 14

Answer 14

Question 15

_________ amino acids are those whose C skeletons are converted to intermediates which can lead to net glucose synthesis (gluconeogenesis)

_________ amino acids are those whose C skeletons are converted to intermediates which cannot lead to glucose synthesis but can lead to the synthesis of fatty acids and ketone bodies

Answer 15

Glucogenic amino acids are those whose C skeletons are converted to intermediates which can lead to net glucose synthesis (gluconeogenesis)

Ketogenic amino acids are those whose C skeletons are converted to intermediates which cannot lead to glucose synthesis but can lead to the synthesis of fatty acids and ketone bodies

Some Amino Acids can be both

Question 16

Extrahepatic tissues can break amino acids down but cannot process the amino groups for excretion as the ________ occurs only in liver

Excess ammonia in tissues is converted to glutamate and glutamine, by the enzymes __________ __________\_ (reductive amination) and _____________ for transport to liver.

Answer 16

Extrahepatic tissues can break amino acids down but cannot process the amino groups for excretion as the urea cycle occurs only in liver

Excess ammonia in tissues is converted to glutamate and glutamine, by the enzymes glutamate dehydrogenase** (reductive amination) and **glutamine synthetase

Question 17

Answer 17

Question 18

Answer 18

Question 19

Regulation of Carbamoyl Phosphate Synthetase (CPS)

• CPS is allosterically activated by N-acetyl glutamate synthesized from acetyl-CoA and glutamate when cellular ________ and _______ levels are high
• Signals high levels of free amino acids and the need to upregulate the urea cycle

Answer 19

Regulation of Carbamoyl Phosphate Synthetase (CPS)

• CPS is allosterically activated by N-acetyl glutamate synthesized from acetyl-CoA and glutamate when cellular glutamate** and **arginine levels are high
• Signals high levels of free amino acids and the need to upregulate the urea cycle

Question 20

Why are disorders of Urea Cycle possibly fatal?

Answer 20

Disorders of the urea cycle are potentially fatal because there is no alternative pathway for urea synthesis and excretion

Question 21

Treatment of Urea Cycle Disorders?

Answer 21

• restrict dietary protein intake
• supplement diet with arginine
• enrich diet with a-ketoacids (carbon skeletons w.o amino group)
• supplement diet with compounds that provide alternative means of nitrogen excretion
• liver transplant

Question 22

Tyrosine synthesized by phenylalanine hydroxylase requires tetrahydrobiopterin (BH4) a cofactor. Phenylalanine hydroxylase deficiency causes ________________. Symptoms?

Answer 22

Tyrosine synthesized by phenylalanine hydroxylase requires tetrahydrobiopterin (BH4) a cofactor. Phenylalanine hydroxylase deficiency causes Phenylketonuria (PKU)

• biochemical screening in newborn babies
• “musty odor” to baby’s sweat and urine
• left untreated, it can cause progressive neurological degeneration,brain damage, and seizures
• lifelong dietary phenylalanine restriction and tyrosine supplementation

Question 23

Metabolism of branched-chain amino acids (______ / _______ / _______) is initiated in ______

Answer 23

Metabolism of branched-chain amino acids (valine / isoleucine / leucine**) is initiated in **muscle

Question 24

What does the absence of branched-chain a-ketoacid dehydrogenase (BCKDH) lead to?

How is this treated?

Answer 24

Genetic deficiency of BCKDH causes Maple syrup urine disease, so called because of the characteristic odour of urine

• Dietary restriction of BRANNCHED CHAIN AMINO ACIDS

Question 25

Key Control points for Regulation of AA Synthesis:

• __________________________
  
  • reductive amination of a-ketoglutarate(incorporation of an amino group from NH4)
  • oxidative deamination of glutamate (removal of amino group as NH4)
  • high levels of ATP /GTP (energy abundance) favours __________ production, anabolic/amino acid, and protein synthesis
  • low energy levels (ADP and/or GDP) favors ____________ production, oxidized via TCA cycle to generate ATP
• _________________________
  
  • Is a key enzyme in controlling the flow of nitrogen into biological molecules
  • Enzyme is subject to cumulative feedback inhibition by at least 8 regulators
  • Is the cell’s Nitrogen Sensor

Answer 25

Key Control points for Regulation of AA Synthesis:

• Glutamate Dehydrogenase (GDH):
  
  • reductive amination of a-ketoglutarate(incorporation of an amino group from NH4)
  • oxidative deamination of glutamate (removal of amino group as NH4)
  • high levels of ATP /GTP (energy abundance) favours glutamate production, anabolic/amino acid, and protein synthesis
  • low energy levels (ADP and/or GDP) favors a-ketoglutarate production, oxidized via TCA cycle to generate ATP
• Glutamine Synthetase (GS):
  
  • Is a key enzyme in controlling the flow of nitrogen into biological molecules
  • Enzyme is subject to cumulative feedback inhibition by at least 8 regulators
  • Is the cell’s Nitrogen Sensor

Question 26

AA Synthesis Overview

Answer 26

Question 27

AA Synthesis Overview (Part 2)

Answer 27