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Metabolism > Nitrogen metabolism > Flashcards

Nitrogen metabolism Flashcards

1
Q

What are the sources of amino acids?

A
  • Digestion of dietary proteins
  • Synthesis of nonessential amino acids
  • Degradation of body proteins
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2
Q

How is the body’s amino acid pool depleted?

A
  • Synthesis of body proteins
  • Consumption for the synthesis of nitrogen-containing small molecules (e.g. prophyrins, creatine, neurotransmitters, hormones, purines, pyrimidines)
  • Conversion of amino acids to glucose, glycogen, fatty acids, ketone bodies, or CO2 + H2O
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3
Q

What is the balance of the inputs and outputs of the amino acid pool in healthy, well-fed individuals?

A

The amino acid pool is in a steady said—the individual is in nitrogen balance

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4
Q

How do proteins vary by rate of degradation?

A
  • For inducibe-expression proteins, regulation of synthesis is more important is more prominent than degradation
  • For constitutively expressed proteins, selective degradation regulates cellular levels of the protein
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5
Q

How much protein is turned over per day?

A

300–400 g

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6
Q

How do proteins vary by half life?

A
  • Minutes–hours: short-lived proteins, usually regulatory or misfolded proteins
  • Days–weeks: the majority of proteins in the cell
  • Months–years: structural proteins (e.g. collagen)
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7
Q

What are the major pathways for cellular degradation of proteins?

A
  • ATP-dependent ubiquitin–proteasome system (cytosol)
  • ATP-independent lysosomal acid hydrolases
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8
Q

How do the ubiquitin–proteasome and lysosomal acid-hydrolase pathways of protein degradation differ?

A
  • Ubiquitin–proteasome pathway: ATP-dependent; degrades endogenous proteins
  • Lysosomal acid-hydrolase pathway: ATP-independent; degrades plasma membrane proteins and endocytosed proteins
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9
Q

What is the mechanism of the ubiquitin–proteasome proteolytic pathway?

A
  1. The protein is selected for degradation by being tagged with molecules of ubiquitin, forming a polyubiquitin chain (consumes ATP → AMP + PPi</sub<)
  2. The ubiquinated proteins are recognized by the proteasome, which unfolds, deubiquinates, and cleaves the protein to fragments (consumes ATP)
  3. The peptide fragments that remain are hydrolyzed to amino acids in the cytosol using non-specific proteases (ATP independent)
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10
Q

What is ubiquitin?

A

A small, globular, non-enzymic protein used for proteolysis

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11
Q

What are the components of the gastric juice that are involved in protein digestion?

A
  • Hydrochloric acid
  • Pepsinogen/pepsin
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12
Q

What cells secrete gastric HCl?

A

Parietal cells

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13
Q

What is the function of HCl in gastric juice?

A
  • Killing bacteria
  • Denaturing proteins, making them more susceptible to hydrolysis by proteases
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14
Q

What cells secrete pepsinogen?

A

Chief cells

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15
Q

What type of protease is pepsin?

A

Endopeptidase

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16
Q

How is pepsin secreted?

A

As the inactive zymogen pepsinogen

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17
Q

How is pepsinogen activated?

A
  • Cleavage using HCl in the stomach
  • Autocatalytically by other pepsin molecules that have already been activated
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18
Q

What are the products of protein digestion in the stomach?

A
  • Peptides
  • A few free amino acids
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19
Q

How is the release and activation of zymogen proteases from the pancreas regulated?

A

By the polypeptide hormones secretin and cholecystokinin

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20
Q

What are the pancreatic enzymes that function in protein digestion in the upper small intestine?

A
  • Trypsin(ogen)
  • Chymotrypsin(ogen)
  • (Pro)Elastase
  • (Pro)Carboxypeptidase
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21
Q

What kinds of proteases are the pancreatic enzymes used in protein digestion?

A
  • Trypsin, chymotrypsin, elastase: serine endopeptidases
  • Carboxypeptidase: C-terminus exopeptidase
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22
Q

How are the pancreatic zymogens used in protein digestion activated?

A
  • Trypsinogen: cleaved by enteropeptidase present on the brush border of the intestinal mucosa
  • Chymotrypsinogen, proelastase, procarboxypeptidase: activated by trypsin
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23
Q

What are the products of protein digestion in the upper small intestine?

(Using pancreatic enzymes)

A
  • Oligopeptides
  • Some free amino acids
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24
Q

How does protein digestion occur in the lower small intestine?

A

N-terminus exopeptidase activity by aminopeptidase on the brush border cleaves the N-terminal residue of oligopeptides, producing amino acids and di- and tripeptides

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25
Q

What are the targets of the proteolytic digestive enzymes other than dietary proteins?

A

These enzymes digest themselves as well as intestinal cells, which are regularly sloughed off into the lumen and replaced

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26
Q

How are amino acids and oligpeptides in the small intestine lumen absorbed?

A
  • Free amino acids: taken up by secondary active transport using a Na+-linked cotransporter
  • Di-/tripeptides: taken up by a H+-linked cotransporter. In the cytosol, these peptides are hydrolyzed to free amino acids
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27
Q

How are free amino acids assimilated after being transported into the mucosal cells of the small intestine?

A
  • The amino acids are released into the hepatic portal vein by facilitated diffusion
  • The amino acids either remain in the general circulation or are metabolized by the liver
  • Branched-chain amino acids (Leu, Ile, Val) are not metabolized by the liver, but instead are sent from the liver to muscle cells via the blood
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28
Q

What are examples of abnormalities of protein digestion and absorption?

A
  • Deficiency in pancreatic secretions (e.g. due to chronic pancreatitis, cystic fibrosis, pancreatectomy), leading to steatorrhea and undigested proteins in the feces
  • Celiac disease
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29
Q

What is the first step in the metabolism of all amino acids?

A

Removal of the α-amino group

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30
Q

How can the α-amino group of amino acids be removed?

A
  • Transamination with an α-keto acid
  • Oxidative deamination
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31
Q

What group of enzymes catalyzes transamination reactions?

A

Aminotransferases (transaminases)

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32
Q

Where are aminotransferases found?

A

The cytosol and mitochondria of cells throughout the body—especially those of the liver, kidney, intestine, and muscle

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33
Q

What is the acceptor of the α-amino group in most transamination reactions? What does it form?

A

α-ketoglutarate → glutamate

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34
Q

What is the equilibrium constant of most transamination reactions?

A

≈ 1

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35
Q

How does the equilbrium of transamination reactions change in physiologic conditions?

A
  • Shifts to amino acid degradation (formation of Glu) after a protein-rich meal
  • Shifts to amino acid formation (deamination of Glu) when the amino acid pool is depleted
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36
Q

What is the reaction catalyzed by alanine aminotransferase (ALT)

A

alanine + α-ketoglutarate ⇌ glutamate + pyruvate

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37
Q

What is the reaction catalyzed by aspartate aminotransferase (AST)?

A

glutamate + oxaloacetate ⇌ aspartate + α-ketoglutarate

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38
Q

Which aminotransferases are particularly important for diagnosis of disease?

A
  • ALT
  • AST
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39
Q

What is the difference between AST and ALT in diagnosis of liver disease?

A
  • ALT is more specific to liver disease as it is found primarily in the liver
  • AST is more sensitive to liver disease as it is found in higher amounts in the liver
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40
Q

In which kinds of diseases may aminotransferases be found in the plasma?

A
  • Viral hepatitis
  • Toxic injury
  • Prolonged circulatory collapse
  • Myocardial infarction
  • Muscle disorders
  • Any conditions causing extensive cell necrosis
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41
Q

Where do oxidative deamination reactions primarily take place?

A
  • Liver
  • Kidneys
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42
Q

What are the general products of oxidative deamination reactions?

A
  • An α-keto acid
  • Free NH3
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43
Q

How is glutamine oxidatively deaminated?

A

glutamate + NAD+ ⇌ α-ketoglutarate + NH3 + NADH
Catalyzed by glutamate dehydrogenase

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44
Q

What coenzymes are needed for the reaction of glutamate dehydrogenase?

A
  • Oxidative deamination (forward): NAD+
  • Reductive amination (reverse): NADPH
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45
Q

How is glutamate dehydrogenase allosterically regulated?

A

Activator

  • GTP (high energy state ⇒ catabolism of amino acids)

Inhibitor

  • ADP (low energy state ⇒ anabolism of amino acids)
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46
Q

What enzyme is used to deaminate ᴅ-amino acids?

A

ᴅ-Amino acid oxidase (DAO)

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47
Q

Where does the DAO reaction occur in the cell?

A

Peroxisome

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48
Q

What is the reaction used to deaminate ᴅ-amino acids in the peroxisome?

A

amino acid + H2O + FAD → α-keto acid + NH3 + FADH2

FAD is regenerated by FADH2 + O2 → FAD + H2O2

Catalyzed by DAO

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49
Q

What medical disorder is linked to increased DAO activity?

A

Increased susceptibility to developing schizophrenia

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50
Q

How is ammonia transported from most tissues to the liver for conversion to urea?

A
  • Ammonia is combined with glutamate in the source tissue to form glutamine by glutamine synthase
  • Glutamine is transported in the blood to the liver
  • Glutamine is cleaved in the liver to form glutamate and free ammonia by glutaminase
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51
Q

How is ammonia from the muscle transported to the liver for conversion to urea?

A
  • α-ketoglutamate is reductively aminated with free ammonia to produce glutamate by glutamate dehydrogenase
  • Glutamate is transaminated with pyruvate to form alanine by ALT
  • Alanine is transported in the blood to the liver
  • Alanine is transaminated in the liver to glutamate, forming pyruvate, by ALT
  • Glutamate is oxidatively deaminated to α-ketoglutarate, liberating free ammonia, by glutamate dehydrogenase
  • To complete the cycle, the pyruvate in the liver is converted to glucose by gluconeogenesis, and this glucose is transported to the liver, where it is broken down to pyruvate
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52
Q

Where in the body does the urea cycle occur?

A

Liver

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53
Q

How many molecules of ammonia are consumed by the urea cycle?

A

Two: one free ammonia (from glutamate), one bound in aspartate

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54
Q

How many molecules of free ammonia are consumed by the urea cycle?

A

One

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55
Q

Where in the cell does the urea cycle occur?

A
  • Mitochondria (steps 1 and 2)
  • Cytosol (steps 3–5)
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56
Q

How many steps are there in the urea cycle (excluding transport across the mitochondrial membrane)?

A

5 steps

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57
Q

What is the first step of the urea cycle?

A

CO2 + NH3 + 2ATP → carbamoyl phosphate + 3H+ + 2ADP + 2Pi
Catalyzed by carbamoyl synthetase 1
Slow, rate-limiting step

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58
Q

What is the second step of the urea cycle?

A

ʟ-ornithine + carbamoyl phosphate → ʟ-citrulline + Pi
Catalyzed by ornithine transcarbamoylase (OTC)

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59
Q

In the Krebs cycle, oxaloacetate is the starting substance that is regenerated at the end of each turn. What is oxaloacetate’s equivalent in the urea cycle?

A

ʟ-ornithine

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60
Q

What is step 3 of the urea cycle?

A

ʟ-citrulline(cyt) + ʟ-aspartate + ATP → argininosuccinate + AMP + PPi
Catalyzed by argininosuccinate synthetase

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61
Q

What is the source of the second ammonia molecule used in the urea cycle?

A

ʟ-Aspartate (obtained from glutamate by transamination)

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62
Q

What is the source of the first ammonia molecule used in the urea cycle?

A

Free ammonia, obtained from:

  • Deamination of glutamate and glutamine
  • Production from urea in the intestine by bacterial urease
  • Catabolism of purines and pyrimidines
  • Metabolism of monoamine hormones and neurotransmitters by amine oxidase
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63
Q

What is the source of ʟ-aspartate used in step 3 of the urea cycle?

A

oxaloacetate + glutamate ⇌ aspartate + α-ketoglutarate
Catalyzed by AST

64
Q

What is step 4 of the urea cycle?

A

argininosuccinate → ʟ-arginine + fumarate
Catalyzed by argininosuccinate lyase

65
Q

What is the fate of fumarate produced by argininosuccinate lyase?

A
  • Transported into the mitochondria for use in the Krebs cycle to produce OAA
  • OAA can be used for gluconeogenesis
  • OAA can be used for transamination again to produce the aspartate needed for the urea cycle
66
Q

What is step 5 of the urea cycle?

A

ʟ-arginine + H2 → ʟ-ornithine + urea
Catalyzed by arginase

67
Q

Where is arginase found?

A

Almost exclusively in the liver

Thus, the urea cycle can be used in other tissues to produce ʟ-arginine as an end product, but urea is only formed in the liver

68
Q

What is the overall reaction of the urea cycle?

A

aspartate + NH3 + CO2 + 3ATP + H2O → urea + fumarate + 2ADP + AMP + 2Pi + PPi

69
Q

How is carbamoyl phosphate synthetase 1 regulated?

A
  • N-Acetylglutamate is an essential activator
  • Arginine is an indirect activator as it activates N-acetylglutamate synthesis
70
Q

How is N-acetylglutamate produced?

A

acetyl CoA + glutamate → N-acetylglutamate + CoA-SH
Catalyzed by N-acetylglutamate synthase, which is activated by arginine

71
Q

What are the fates of urea?

A
  • Diffusion out of the liver to the blood, where it is filtered through the kidneys into urine for excretion
  • Diffusion from the blood into the intestine, where it is cleaved by bacterial urease into CO2 and NH3. The ammonia is partially reabsorbed into the blood and partially lost in the feces
72
Q

What is the diagnostic criterion of hyperammonemia?

A

﹥35 μmol L–1

73
Q

What are the effects of hyperamonnemia?

A

Neurotoxicity on the CNS:

  • Tremors
  • Slurred speech
  • Somnolence
  • Vomiting
  • Cerebral edema
  • Blurred vision
  • Coma
  • Death
74
Q

What are the types of hyperammonemia?

A
  • Congenital
  • Acquired
75
Q

What is the etiology of acquired hyperammonemia?

A

Liver disease, e.g. from hepatitis or hepatotoxins like alcohol

This leads to a collateral circulation around the liver, so ammonia is shunted directly into the systemic circulation and has no access to the liver

76
Q

What is the etiology of congenital hyperammonemia?

A

Genetic deficiencies in any of the five enzymes involved in the urea cycle, of which OTC deficiency is the most common

77
Q

What is the inheritance pattern of ornithine transcarbamoylase (OTC) deficiency?

A

X-linked recessive

78
Q

How is congenital hyperammonemia treated?

A
  • Restriction of dietary protein in the presence of sufficient calories to prevent catabolism
  • Administration of compounds that bind covalently to amino acids, producing molecules that are excreted in the urine (e.g. the prodrug phenylbutyrate, which is converted to phenylacetate and condenses with glutamine)
79
Q

What are the functions and uses of ribonucleosides and deoxyribonucleosides?

A
  • Synthesis of RNA and DNA
  • Carriers of activated intermediates in synthesis of some carbohydrates, lipids, and conjugated proteins, e.g. UDP-glucose
  • Structural components of several coenzymes, e.g. coenzyme A, FAD, NAD+
  • cAMP and cGMP function as second messengers
  • Nucleotides are energy currency molecules
  • Nucleotides are important regulatory compounds in metabolic reactions
80
Q

How are purine and pyrimidine bases obtained in the cell?

A
  • Synthesized de novo
  • Obtained through salvage pathways from preformed bases
  • Obtained ready-formed through the diet (this is a very minor source)
81
Q

What are the purines?

A
  • Adenine (A)
  • Guanine (G)
82
Q

What are the pyrimidines?

A
  • Cytosine (C)
  • Uracil (U)
  • Thymine (T)
83
Q

How can nitrogenous bases be modified?

A
  • Acetylation (usually activates the gene)
  • Reduction
  • Methylation (usually silences the gene)
  • Glycosylation
84
Q

What is a nucleoside?

A

A pentose sugar with a nitrogenous base, whether a ribonucleoside or a deoxyribonucleoside

85
Q

What is a nucleotide?

A

A nucleotide attached to 1, 2, or 3 phosphate groups ([deoxy-]nucleoside mono-, di-, and triphosphates)

86
Q

Which carbon of the pentose is attached to the nitrogenous base?

A

1’ carbon

87
Q

Which carbon of the pentose is attached to the phosphate(s)?

A

5’ carbon

88
Q

Which bonds in nucleoside triphosphates are high-energy?

A

The bond between phosphate 3 and phosphate 2, and the one between phosphate 2 and phosphate 1 (where 3 is the one furthest from the pentose)

89
Q

What are the sources of elements in the synthesis of purines?

A
  • Aspartate
  • Glycine
  • Glutamine (twice)
  • CO2
  • N10-formyl-tetrahydrofolate (twice)
90
Q

What is the first step in synthesis of purine nucleotides?

A

ribose-5-phosphate + ATP → 5-phosphoribosyl-1-pyrophosphate (PRPP) + AMP
Catalyzed by PRPP synthetase (ribose phosphate pyrophosphokinase)

91
Q

How is PRPP synthetase regulated?

A

Activators

Pi

Inhibitors

Purine nucleotides (end-product inhibition)

92
Q

What is the committed step in purine nucleotide biosynthesis?

A

Step 2, where the amide group of glutamine replaces the pyrophosphate on carbon 1 of PRPP

93
Q

How is the committed step of purine nucleotide synthesis regulated?

A

Inhibitors

  • AMP (end-product inhibition)
  • GMP (end-product inhibition)
94
Q

What is the end-product of the common reactions in the synthesis of GMP and AMP?

A

Inosine monophosphate (IMP)

95
Q

What is the nitrogenous base of inosine monophosphate?

A

Hypoxanthine

96
Q

What is the sequence of modifications to PRPP resulting in the formation of IMP?

A

(Order not required)

  • Glutamine transfers an amino group
  • Glycine is incorporated in full
  • N10-formyl-tetrahydrofolate transfers a formyl group
  • Glutamine transfers an amide group
  • CO2 is incorporated
  • Aspartate is incorporated in full then removed as fumarate, giving a net transfer of an amino group
  • N10-formyl-tetrahydrofolate transfers a formyl group
97
Q

How is IMP converted to AMP?

A

(1) IMP + GTP + aspartate → adenylosuccinate + GDP + Pi
(2) adenylosuccinate → AMP + fumarate

(1) catalyzed by adenylosuccinate synthetase
(2) catalyzed by adenylosuccinase

98
Q

How is IMP converted to GMP?

A

(1) IMP + H2O + NAD+ → xanthosine monophosphate + NADH + H+
(2) xanthosine monophosphate + ATP + glutamine → GMP + glutamine + AMP + PPi

(1) catalyzed by IMP dehydrogenase
(2) catalyzed by GMP synthetase

99
Q

How are purine nucleoside monophosphates converted to nucleoside diphosphates?

A

AMP + ATP ⇌ 2ADP (adenylate kinase)
GMP + ATP ⇌ GDP + ADP (guanylate kinase)

100
Q

How are nucleoside diphosphates converted to nucleoside triphosphates?

A

Interconversion by the nonspecific enzyme nucleoside diphosphate kinase, e.g.
GDP + ATP ⇌ GTP + ADP

101
Q

Where is adenylate kinase found in high concentrations?

A

The liver and muscle, where turnover of ATP energy is high

102
Q

What are the synthetic inhibitors of purine synthesis?

A
  • Sulfonamides: inhibit purine synthesis is bacteria
  • Methotrexate: a folic acid analog that inhibits purine synthesis in human cells (anticancer drug)
103
Q

What cells other than tumors are greatly affected by methotrexate?

A
  • Fetal cells
  • Bone marrow
  • Skin
  • GI tract
  • Immune system
  • Hair follicles
104
Q

What are the general adverse effects of cancer drugs?

A
  • Anemia
  • Hair loss
  • Scaly skin
  • GI tract disturbance
  • Immunodeficiencies
105
Q

How are ribonucleotides converted to deoxyribonucleotides?

A

ribonucleoside diphosphate → deoxyribonucleoside diphosphate + H2O
Catalyzed by ribonucleotide reductase, which donates the hydrogens

106
Q

How is reduced ribonucleotide reductase regenerated?

A

Thioredoxin, which has 2 thiol groups (2 SH), is oxidized (S–S)

107
Q

How is thioredoxin regenerated for use with ribonucleotide reductase?

A

thioredoxin S–S + NADPH + H+ ⇌ thioredoxin 2 SH + NADP+
Catalyzed by thioredoxin reductase

108
Q

How is ribonucleotide reductase regulated?

A

Activators

ATP: binds to activity sites, increasing overal catalytic activity

Inhibitors

dATP (end-product inhibition): binds to activity sites, inhibiting overal catalytic activity

Other

Binding of a dNTP to substrate specificity sites changes the specificity of the enzyme to a specific species of ribonucleotide. E.g. binding of dTTP causes a conformational change that allows reduction of GDP to dGDP

109
Q

How many subunits is ribonucleotide reductase composed of?

A

Four: two R1 subunits, two R2 subunits

110
Q

What is the function of the drug hydroxyurea?

A
  • Destroys the free radical needed for the function of ribonucleotide reductase, thus inhibiting DNA synthesis
  • Used in treatment of cancers such as chronic myelogenous leukemia
111
Q

Where in the body are dietary nucleic acids degraded?

A

Small intestine

112
Q

What are the enzymes involved in dietary nucleic-acid degradation?

A
  • Pancreatic ribonucleases and deoxyribonucleases: hydrolyze RNA and DNA to oligonucleotides
  • Pancreatic phosphodiesterases: hydrolyze oligonucleotides to 3’- and 5’-mononucleotides
  • Brush border nucleotidases: hydrolyze the phosphoester bond, removing the phosphate and releasing nucleosides
113
Q

What is the fate of most purine nitrogenous bases obtained in the diet?

A

Converted to uric acid in the small intestine mucosa and excreted in the urine

114
Q

How is AMP degraded in the small intestine mucosa?

A

Pathway 1

(1) AMP + H2O → IMP + NH3 (AMP deaminase)
(2) IMP + H2O → inosine + Pi (5’-nucleotidase)
(3) inosine + Pi → hypoxanthine + ribose-5-phosphate (purine nucleoside phosphorylase)
(4) hypoxanthine + H2O + O2 → xanthine + H2O2 (xanthine oxidase)
(5) xanthine + H2O + O2 → uric acid + H2O2 (xanthine oxidase)

Pathway 2

(1) AMP + H2O → adenosine + Pi (5’-nucleotidase)
(2) adenosine + H2O → inosine + NH3 (adenosine deaminase)
inosine then merges with pathway 1 in step 3

115
Q

How is GMP degraded in the small intestine mucosa?

A

(1) GMP + H2O → guanosine + Pi (5’-nucleotidase)
(2) guanosine + Pi → guanine + ribose-5-phosphate (purine nucleoside phosphorylase)
(3) guanine + H2O → xanthine + NH3 (guanase)
(4) xanthine + H2O + O2 → uric acid + H2O2 (xanthine oxidase)

116
Q

Where do the degradative pathways of AMP and GMP meet?

A

At the formation of xanthine, which is then converted to uric acid

117
Q

What is the cause of gout?

A
  • High levels of uric acid in the blood (hyperuricemia)
  • Hyperuricemia leads to deposition of sodium urate crystals in the joints, which triggers an acute inflammatory reaction, which can progress to chronic gouty arthritis
  • Sometimes, nodular masses of monosodium urate crystals (tophi) are deposited in soft tissues, resulting in chronic tophaceous gout
  • Uric acid kidney stones (urolithiasis) may also be seen
118
Q

How is gout definitively diagnosed?

A
  • Aspiration and examination of synovial fluid from an affected joint (or from a tophus)
  • Using light microscopy to confirm presence of needle-shaped monosodium urate crystals
119
Q

What are the mechanisms that lead to hyperuricemia?

A
  • Underexcretion of uric acid (the typical cause): either due to primary or secondary causes
  • Overproduction of uric acid: due sometimes to a rare mutation in X-linked PRPP synthetase, resulting in an overactive enzyme that causes high levels of purine nucleotides, resulting in hyperuricemia
120
Q

What are the causes of underexcretion of uric acid?

A
  • Primary causes: unidentified inherent excretory defects
  • Secondary causes affecting the kidney:
    • Lactic acidosis: lactate and uric acid compete for the same renal transporter
    • Use of drugs, e.g. thiazide diuretics
    • Exposure to lead (saturnine gout)
121
Q

What is the name of the type of gout caused by exposure to lead/

A

Saturnine gout

122
Q

What are the common required substrates for synthesis of purine nucleotides and pyrimidine nucleotides (ignoring molecules required only for energy or redox)?

A
  • Glutamine
  • Aspartic acid
  • PRPP
  • CO2 (which is regenerated)
123
Q

How does the sequence of pyrimidine nucleotide synthesis differ from that of purines?

A
  • For pyrimidines, the nitrogenous base is completed first then transferred to the pentose
  • For purines, the nitrogenous base is synthesized on the pentose
124
Q

What are the steps of pyrimidine nucleotide synthesis, ending in UMP?

A

(1) 2ATP + CO2 + glutamine → carbamoyl phosphate + 2ADP + Pi + glutamate (carbamoyl phosphate synthetase II)
(2) carbamoyl phosphate + aspartate → carbamoyl aspartate + Pi (aspartate transcarbamoylase)
(3) carbamoyl aspartate + H+ → dihydroorotate + H2O (dihydroorotase)
(4) dihydroorotate + FAD → orotate + FADH2 (dihydroorotate dehydrogenase)
(5) orotate + PRPP → orotidine 5’-monophosphate + PPi (orotate phosphoribosyltransferase)
(6) OMP → UMP + CO2 (OMP decarboxylase)

125
Q

What are the domains of the enzyme CAD?

A
  • Carbamoyl phosphate synthetase II
  • Aspartate transcarbamoylase
  • Dihydroorotase
126
Q

What is special about the enzyme dihydroorotase?

A

It is associated with the inner mitochondrial membrane. All other enzymes in pyrimidine biosynthesis are cytosolic

127
Q

What are the domains of the enzyme UMP synthetase?

A
  • Orotate phosphoribosyltransferase
  • OMP decarboxylase (orotidylate decarboxylase)
128
Q

What is orotic aciduria?

A

A rare genetic defect caused by deficiency in one or both activities of UMP synthetase, leading to orotic acid in the urine

129
Q

What is the fate of UMP synthesized de novo?

A
  • Phosphorylated to UDP by uridylate kinase
  • UDP is phosphorylated to UTP by a nonspecific nucleoside diphosphate kinase
  • UDP is reduced to dUDP by ribonucleotide reductase
  • dUDP is phosphorylated to dUTP
  • dUTP is rapidly degraded to dUMP by dUTPase so that it isn’t accidentally incorporated into DNA
130
Q

How is CTP synthesized?

A

UTP + ATP + glutamine → CTP + ADP + Pi + glutamate
Catalyzed by CTP synthetase

131
Q

How is TMP synthesized?

A

dUMP + N5,N10-methylene-tetrahydrofolate → dTMP + dihydrofolate
Catalyzed by thymidylate synthase

132
Q

The synthesis of TMP leads to the production of dihydrofolate as a byproduct. What is the metabolic fate of dihydrofolate?

A

dihydrofolate + NADPH + H+ → tetrahydrofolate + NADP+
Catalyzed by dihydrofolate reductase

133
Q

How does 5-fluorouracil act as an anticancer drug?

A
  • 5-fluorouracil is converted to 5-FdUMP
  • 5-FdUMP becomes permanently bound to thymidylate synthase, inactivating it (it is therefore a suicide inhibitor)
134
Q

How does methotrexate function as an anticancer drug?

A

It inhibits dihydrofolate reductase, meaning tetrahydrofolate cannot be regenerated for use in purine or pyrimidine synthesis. The affected nucleotides are both purines (A and G) and T

135
Q

Which pyrimidine nucleotide can be salvaged?

136
Q

How is adenosine salvaged?

A

Adenosine is phosphorylated to AMP (using ATP) using a kinase

137
Q

How are pyrimidines degraded?

A

The pyrimidine ring is directly opened and degraded to the highly soluble β-alanine and β-aminoisobutyrate, with the production of NH3 and CO2

138
Q

What are the glucogenic amino acids?

A
  • Alanine
  • Arginine
  • Aspartate
  • Cysteine
  • Glutamate
  • Glutamine
  • Glycine
  • Proline
  • Serine
  • Histidine
  • Methionine
  • Threonine
  • Valine
  • Tyrosine
  • Isoleucine
  • Phenylalanine
  • Tryptophan

(18)

139
Q

What are the ketogenic amino acids?

A
  • Tyrosine
  • Isoleucine
  • Phenylalanine
  • Tryptophan
  • Leucine
  • Lysine
139
Q

Which amino acids are both glucogenic and ketogenic?

A
  • Tyrosine
  • Isoleucine
  • Phenylalanine
  • Tryptophan
140
Q

Which amino acids are essential?

A
  • Histidine
  • Methionine
  • Threonine
  • Valine
  • Isoleucine
  • Phenylalanine
  • Tryptophan
  • Leucine
  • Lysine

(9)

141
Q

Which amino acids yield oxaloacetate?

A
  • Asparagine: hydrolytically deaminated to Asp by asparaginase
  • Aspartate: transaminated by AST
142
Q

Which amino acids yield α-ketoglutarate?

A
  • Glutamine: hydrolytically deaminated to Glu by glutaminase
  • Proline: oxidized to Glu
  • Arginine: hydrolyzed to ornithine by arginase, which is converted to α-KG
  • Histidine: oxidatively deaminated by histidase
  • Glutamate: transaminated to α-KG
143
Q

Which amino acids yield fumarate?

A
  • Phenylalanine: hydroxylated to tyrosine by phenylalanine hydroxylase, using tetrahydrobiopterin
  • Tyrosine: converted to fumarate or acetoacetate
144
Q

How is tetrahydrobiopterin recycled for use in amino acid metabolism?

A

Dihydrobiopteridine reductase

145
Q

Which amino acids yield pyruvate?

A
  • Alanine: transamination with Glu
  • Serine: by serine dehydratase, producing water and ammonium
  • Glycine: converted to Ser by addition of a methylene group using N5,N10-methylene-THF
  • Cystine (Cys-S–S-Cys): reduced to Cys (Cys-SH) using NADH. Cys is desulfurated to pyruvate
  • Threonine: converted to pyruvate or α-ketobutyrate (which forms succinyl CoA)
146
Q

Which amino acids yield succinyl CoA?

A
  • Valine: generates proprionyl CoA, which is converted to succinyl CoA using biotin and vitamin B12
  • Isoleucine: generates proprionyl CoA, which is converted to succinyl CoA using biotin and vitamin B12
  • Threonine: dehydrated to α-ketobutyrate, which forms succinyl CoA
  • Methionine
147
Q

Which amino acids yield acetyl CoA or acetoacetyl CoA?

A
  • Leucine
  • Isoleucine
  • Lysine
  • Tryptophan
148
Q

Which amino acids are nonessential?

A
  • All the A’s: Asp, Asn, Ala, Arg
  • All the G’s: Glu, Gln, Gly
  • Cysteine
  • Proline
  • Serine
  • Tyrosine
149
Q

Which nonessential amino acids are formed by transamination?

A
  • Alanine: from pyruvate
  • Aspartate: from oxaloacetate
  • Glutamate: from α-KG
150
Q

How is glutamine synthesized?

A

Amidation of glutamate
glutamate + ATP + NH3 → glutamine + ADP + Pi (glutamine synthetase)

151
Q

How is asparagine synthesized?

A

Amidation of aspartate
aspartate + ATP + glutamine → asparagine + ADP + Pi + glutamate (glutamine synthetase)

152
Q

How is proline synthesized?

A

(1) glutamate + ATP + NADH → intermediate 1 (reduction)
(2) intermediate 1 → intermediate 2 (dehydration and cyclization)
(3) intermediate 2 + NADPH → proline (reduction)

153
Q

How is serine synthesized?

A

(1) 3-phosphoglycerate → 3-phosphopyruvate (oxidation)
(2) 3-phosphopyruvate → 3-phosphoserine (transamination)
(3) 3-phosphoserine → serine (phosphatase hydrolysis)

Or, addition of hydroxymethyl to glycine by N5,N10-methylene-THF

154
Q

How is glycine synthesized?

A

Transfer of hydroxymethyl from serine to THF

155
Q

How is cysteine synthesized?

A

(1) Addition of serine to homocysteine, using B6, forming cystathionine
(2) Hydrolysis of cystathionine, yielding Cys and α-ketobutyrate

156
Q

How is tyrosine synthesized?

A

Hydroxylation of phenylalanine by phenylalanine hydroxylase, using tetrahydrobiopterin

Metabolism (6 decks)

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