Nitrogen, Amino Acids and the Urea Cycle

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1

The first phase of amino acid catabolism involves...?

The removal of the α-amino groups (usually by transamination and subsequent oxidative deamination).

2

What are the products of the usual first phase of amino acid catabolism (transamination and subsequent oxidative deamination)?

Ammonia and the corresponding α-keto acid- the "carbons skeletons" of amino acids.

3

A portion of the free ammonia is excreted in urine. Where does the rest of it go?

Most is used in the synthesis of urea.

4

What is the purpose of urea?

It is the most important route for disposing of nitrogen from the body.

5

What is the second phase of amino acid catabolism?

The carbon skeletons of the α-keto acids are converted to common intermediates of energy producing metabolic pathways. (The compounds are metabolized to CO2, water, glucose, fatty acids, or ketone bodies).

6

What is the amino acid pool?

All the free amino acids in the body, in cells, blood, and extracellular fluid.

7

What are the three inputs into the amino acid pool?

1. Degradation of body proteins
2. AA's derived from dietary protein
3. Synthesis of nonessential AAs from simple intermediates of metabolism.

8

What are the 3 outputs of the amino acid pool?

1. Synthesis of body protein
2. AA's consumed as precursors of essential N-containing small molecules
3. Conversion of AA's to glucose, glycogen, fatty acids, ketone bodies, or CO2+H2O.

9

What can be said of the inputs and outputs to the amino acid pool in a healthy person?

They are equal, i.e. the person is in nitrogen balance.

10

Describe the general structure of an amino acid.

α-amino carboxylic acid

11

Amino acids are α amino carboxylic acids. All non essential amino acids are derived from...?

Corresponding α-keto acids

12

α amino carboxylic acids are derived from corresponding α-keto acids via...?

Transamination or direact amination involving activation.

13

Naturally occuring amino acids are in the (D/L) configuration.

L-configuration

14

What two amino acids feed the carbon backbone into pathways that lead to fatty acyl precursor and keto acids that don't lead to glucose?

Lysine and Leucine
(called ketogenic AA's)

15

What is the mnemonic for remembering the essential amino acids?

PVT TIM HALL

16

What are the essential amino acids?

P- Phenylalanine
V- Valine
T- Threonine
T- Tryptophan
I- Isoleucine
M- Methionine
H- Histidine
A- Arginine
L- Leucine
L- Lysine

17

All of the essential α-amino AA's are converted to ________ for inter conversion and metabolism.

The corresponding α-keto acid

18

Which essential amino acid is only required during growth?

Arginine

19

Non-essential amino acids are derived from...?

Modification of metabolic intermediates from glycolysis and the TCA cycle.

20

What are the modifications (to the metabolic intermediates from glycolysis and the TCA cycle) that derive non-essential amino acids?

Transfer of amino groups and sulfur

21

What is the source in metabolism of: Alanine?

From pyruvate via transamination

22

What is the source in metabolism of: Aspartic acid, asparagine, arginine, glutamic acid, glutamine, proline?

From intermediates in the TCA cycle.

23

What is the source in metabolism of: Serine?

From 3-phosphoglycerate (glycolysis)

24

What is the source in metabolism of: Glycine?

Serine

25

What is the source in metabolism of: Cysteine?

Serine; requires sulfur derived from methionine

26

What is the source in metabolism of: Tyrosine?

Derived from phenylalanine via hydroxylation

27

What is the source of essential amino acids?

Dietary protein supplies essential AA's that are released as free AA's via digestion in the gut and small intestine.

28

What is the source of AA's during malnutrition, starvation, and essential amino acid deficiency?

Muscle protein

29

Nitrogen is removed from amino acids by three different enzymes to yield carbon backbones used for energy. What are these three reactions?

Transamination
Oxidative deamination
Removal of water by hydratase

30

What is the major process for moving Nitrogen among amino acids?

Transamination

31

___________ is the major participant in transaminations. The "gateway" between amino groups and free ammonia.

Glutamate.

32

All amino acids except _______ and _________ undergo transaminations.

Lysine
Threonine

33

How then do lysine and threonine lose their α-amino groups?

Deamination
(discussed later)

34

What class of enzyme is responsible for transaminations?

Aminotransferases
(formerly called transaminases)

35

What is the major cofactor of transamination reactions?

Pyridoxyl phosphate (PLP)

36

____________ plays a major role in amino acid metabolism by accepting the amino groups from most AA's, thus becoming glutamate.

α-ketoglutarate

37

When an amino acid transfers its α-amino group to α-ketoglutarate (which becomes glutamate), the product is an ____________ (derived from the original AA).

α-keto acid

38

Describe the nature and location of pyridoxal phosphate (PLP)

PLP is the functional enzyme form of vitamin B6.
It is covalently bound to aminotransferase. This linkage is displaced by the incoming NH2 of the amino acid aspartate or glutamate.

39

Where are aminotransferases normally located?

In the liver.

40

High levels of aminotransferases in serum indicate...?

Liver damage.

41

__________ is formed when the α-keto acid is released.

Pyridoxamine

42

What are the key α-keto acid intermediates in the interconversion of carbon backbones between amino acids and intermediary metabolites and the urea cycle?

Pyruvate
α-ketoglutarate
oxaloacetate

43

As a review, what reaction involves the transfer of an amino group to a keto acid?

Transamination

44

In contrast to transamination reactions, what reaction results in the liberation of the amino group as free ammonia, replacing the amino group with oxygen from O2?

Oxidative deamination.

45

What two things can happen in a dehydratase reaction?

Water is removed to form an imine.
Water is added back to form a keto acid and ammonia.

46

Where in the body do oxidative deamination reactions occur?

In the liver and kidney

47

What enzyme catalyzes oxidative deamination?

Glutamate dehydrogenase

48

What co-factor is required for oxidative deamination?

Flavin mononucleotide (FMN)

49

What are the products of oxidative deamination?

α-keto acids and ammonia

50

What is the only amino acid that undergoes rapid oxidative deamination?

Glutamate, of course.
The amino groups of most amino acids are funneled to glutamate by transamination with α-ketoglutarate. Thus transamination and oxidative deamination are a pathway whereby amino groups of most amino acids are released as ammonia.

51

Dehydratase reactions remove a water and work exclusively with what type of amino acid?

Hydroxyamino acids: serine and threonine

52

Liver ammonia is incorporated into _____________ by ____________.

Glutamate; glutamate dehydrogenase

53

__________ is the "gateway" for the distribution of amino groups into most amino acids.

Glutamate

54

The oxidative deamination of glutamate to α-ketoglutarate (w/ release of ammonia) is allosterically stimulated by (ADP and GDP / ATP and GTP).

ADP and GDP.

55

Glutamate dehydrogenase can use either NAD+ or NADP+ as a coenzyme. Which is used primarily in oxidative deamination?

NAD+

56

When is NADPH used?

In the reductive amination of α-ketoglutarate to glutamate.

57

There is an equilibrium between glutamate and α-ketoglutarate/NH4+. Which direction does the reaction usually run?

In the direction of α-ketoglutarate formation, for carbohydrate metabolism.

58

Some amino acids can be synthesized in humans provided that glucose and a nitrogen source is available. What is an example of this?

Pyruvate to alanine.

59

Nitrogen from cells and bacteria in the gut generate toxic __________.

Ammonia.

60

_______ is reversible and can release or incorporate ammonium to or from glutamate.

Glutamate dehydrogenase (GDH)

61

What three enzymes fix nitrogen into biomolecules?

GDH
Glutamine synthetase
Carbamoyl phosphate synthetase

62

During metabolic interconversions of amino acids, the amino group of alanine is transferred to ________ to yield _________ and ________.

α-ketoglutarate
To yield pyruvate and glutamate

63

What is the purpose of transamination of alanine to yield pyruvate (converting α-ketoglutarate to glutamate in the process)?

An amino acid is lost and a glycolytic intermediate is generated, leading to oxidation and energy production

64

All transamination reactions involve _________ and __________.

α-ketoglutarate and glutamate

65

Describe the transport of ammonia from peripheral tissues to the liver for its ultimate conversion to urea.

Glutamine synthetase combines ammonia (NH4+) with glutamate to form glutamine- a non-toxic transport form of ammonia. In the liver, glutaminase cleaves glutamine to form glutamate and free ammonia.

66

What is the first step in the urea cycle?

In the mitochondrial matrix, carbamoyl phosphate is formed from ammonia and CO2 and ATP by carbamoyl phosphate synthetase I (CPSI)

67

What is the absolute requirement of carbamoyl phosphate synthetase I (CPSI)?

N-acetyl-glutamate is required as a positive allosteric activator.

68

What is the second step in the urea cycle?

Formation of citrulline.

69

Describe the formation of citrulline.

The carbamoyl portion of carbamoyl phosphate is transferred to ornithine by ornithine transcarbamoylase to form citrulline, which is transported to the cytosol.

70

What is the third step of the urea cycle?

The synthesis of arginosuccinate.

71

Describe the synthesis of arginosuccinate.

Arginosuccinate synthase combines citrulline with aspartate to form arginosuccinate.

72

What is the fourth step of the urea cycle?

The cleavage of arginosuccinate to yield arginine.

73

Describe the cleavage of arginosuccinate.

Arginosuccinate is cleaved by arginosuccinate lyase to yield arginine and fumarate. The arginine serves as the immediate precursor of urea. Fumarate is hydrated to malate providing a link to several metabolic pathways.

74

What is the final step of the urea cycle?

Cleavage of arginine to urea and ornithine.

75

What enzyme cleaves arginine to form urea (and ornithine)?

Arginase.

76

Defects in any of the enzymes of the urea cycle leads to ____________ and excess precursor molecules.

Hyperammonemia.

77

How is hyperammonemia treated?

Drugs to condense ammonia into glycine or glutamine
Limit nitrogen intake
Feed with α-keto acids

78

What happens when the mitochondrial CPSI is limiting or defective due to defects in the mitochondrial ornithine transcarbamoylase (OTC)?

Nitrogen is driven through CPSII in the cytosol, in the pyrimidine pathway to form orotic acid which is detected in the blood and urine.

79

The urea cycle is (up/down)regulated by a high protein diet, and (up/down)regulated by a high carbohydrate diet.

Upregulated by protein diet
Downregulated by carbohydrate diet.

80

The urea cycle is (up/down)regulated during starvation.

Upregulated.

81

Short-term regulation of the urea cycle is by activation of CPSI (the enzyme just prior to the urea cycle) by its required allosteric activator N-acetylglutamate. High levels of ________ stimulate production of N-acetylglutamate.

Arginine. The immediate precursor to urea.

82

Knowing that N-acetylgulatamate is required for CPSI activity, what is required for production of N-acetylglutamate?

Arginine.

83

What is the most common of the urea cycle enzyme deficiencies?

Ornithine transcarbamoylase (OTC)

84

What is the most abundant circulating amino acid? Why?

Glutamine. This is because free ammonia is toxic and is incorporated into glutamine by glutamine synthetase (ATP required, starting material is glutamate).

85

The primary nitrogenous excretion product in urine is:

Urea

86

A compound common to the urea cycle and the TCA cycle is:

Fumarate

87

Which amino acid has an important role in the transport of amino groups from peripheral tissues to the liver?

Glutamine

88

Which enzyme will directly fix NH4 into biomolecules?

Glutamine synthetase