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SFM Exam 2 > Protein And AA Metabolism > Flashcards

Protein And AA Metabolism Flashcards

1
Q

What are inborn errors of metabolism?

A

Conditions associated with dysfunctional metabolism of amino acids and derivatives

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2
Q

What is an amino acid pool?

A

Population of free amino acids supplied by protein turnover, digested food and de novo synthesis (of NE aa)

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3
Q

What is the amino acid pool depleted by?

A

Production of body protein, synthesis of N containing compounds and degradation

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4
Q

Which amino acids are considered conditionally essential?

A

Arg (prematurity), Cys, Gly, Gln, Pro and Tyr

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5
Q

What is the major source of nitrogen?

A

Dietary protein

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6
Q

What are the major nitrogen excretory compounds?

A

Urea, ammonia, creatine (muscle), uric acid (purine breakdown product) and urobilinogen (heme metabolism)

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7
Q

How many g of protein is needed to maintain the amino acid pool?

A

30g of protein per day

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8
Q

Characteristics of Hartnup and Cystinuria

A

Protein transporters mediate transport of amino acids in and out of cells
Both are autosomal recessive conditions that are associated with defects in these transporters

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9
Q

Describe Hartnup disease**

A

Defective transport of nonpolar or neutral amino acids (e.g. tryptophan) leading to concentrated level in the urine
Transporter located in the kidney and SI
Manifests in infancy with failure to thrive, nystagmus, tremor, intermittent ataxia and photosensitivity

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10
Q

Describe Cystinuria

A

Defective transport of dimeric cystine and dibasic amino acids Arg, Lys and ornithine
Formation of cystine crystals in the kidneys (renal calculi)
Pts present with renal colic, which is abdominal pain that comes in waves and is liked to the formation of kidney stones

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11
Q

What can overcome the deficiency of transport of neutral amino acids in most patients with Hartnup disease?

A

A high protein diet

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12
Q

Biosynthesis of aromatic amino acids Try and Trp

A

Phe —> Tyr

Ribose 5 P —> His

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13
Q

Biosynthesis of serine

A

3PG —> Ser —> Cys or Gly

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14
Q

Biosynthesis of aspartate

A

OAA —> Asp —> Asn

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15
Q

Biosynthesis of glutamate

A

Alpha ketoglutarate —> Glu —> Gln, Pro and Arg

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16
Q

The biosynthesis of amino acids involves what type of reaction?

A

Transamination reaction from an alpha keto acid

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17
Q

What are the three protein degradation pathways?

A

Proteasome, lysosome and autophagosome

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18
Q

Describe the lysosomal/autophagy pathway of protein degradation

A

Lysosomes sequester >50 hydrolase-type intracellular proteolytic enzymes that are active at pH of 5 (in the lysosome) and inactive at pH 7 (cytoplasmic)
Non-selective
3 types: macroautophagy, macroautophagy and chaperone mediated autophagy (CMA)

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19
Q

What is the common denominator in the targeting of substrates in all three protein degradation pathways?

A

Ubiquitin

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20
Q

Describe proteasomal degradation

A

Large proteasome cytoplasmic complexes cleave polyubiquitinated proteins —> ubiquitin pathway

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21
Q

What is the signal for proteolysis in the proteasome?

A

Ubiquitin

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22
Q

Structure of the proteasome

A

Catalytic core = 20s
Each ring consists of 7 subunits that are stacked to form a barrel
Active sites are hidden inside the barrel so something must be ushered into the catalytic core
19s regulatory subunit attached to both ends fo the catalytic subunit and contains ubiquitin receptors

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23
Q

What is the role of isopeptidase in the proteasomal degradation pathway?

A

It cleaves ubiquitin in the regulatory unit for reuse so the cell doesn’t have to make more Ubq

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24
Q

What is the nucleophile in the proteasomal degradation pathway?

A

OH of threonine acts as a nucleophile to attach carbonyl of peptide bonds degraded to peptides ranging from 7-9 amino residues

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25
Q

Describe extracellular proteolytic control

A

Proteolytic enzymes are secreted as inactive zymogens as needed
Activated by proteolytic cleavage
Enterokinases are embedded in the intestinal mucosa

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26
Q

Example of extracellular proteolytic control

A

Inactive trypsinogen and chymotrypsinogen are released into the SI lumen
Trypsinogen is activated by an enterokinase, enteropeptidase
Trypsin activates chymotrypsinogen and other molecules of trypsinogen

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27
Q

Amino acids can be classified by what?

A

By what they are metabolized to

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28
Q

Describe ketogenic amino acids

A

Can be deaminated to produce alpha keto acids and KBs —> fatty acids
Alpha keto acids and KBs cannot be metabolized into glucose (both carbonyl carbons are metabolized to CO2 in the TCA cycle)

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29
Q

Which amino acids are ketogenic only?

A

Leu and Lys

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30
Q

Which amino acids are both ketogenic and glucogenic?

A

Ile, Trp, Phe, Tyr and Thr

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31
Q

Which amino acids are glucogenic only?

A

Val, His, Arg, Asn, Gln, Met, Ala, Asp, Glu, Gly, Pro, Ser, Cys

32
Q

Glucogenic amino acids are eventually converted into what?

A

Glucose

33
Q

What are the three most important reactions/enzymes in amino acid metabolism?

A
  1. Aminotransferase/transaminase
  2. Glutamate dehydrogenase (oxidative deamination)
  3. Urea cycle
34
Q

True or false: Every amino acid has a conjugate keto acid

A

True

35
Q

OAA is the keto acid of which amino acid?

A

Aspartate

36
Q

The amine group of amino acids is shuffled into the

A

Liver as other amino acids then repackaged as urea in the urea cycle and excreted

37
Q

Describe the shuffling of amino acids through transamination

A

Amino group is transferred to an alpha keto acid
Coupled reactions
Enzymes = transaminases/aminotransferases

38
Q

Describe transaminases (aminotransferases)

A

Require coenzyme pyridoxal 5’-phosphate (PLP) which is a derivative of vitamin B6
Clinical relevance: ALT and AST

39
Q

Describe how amino transferases are used in a clinical setting

A

Located in mitochondria, and cytoplasm of liver, kidney, intestine and muscle cells
+aminotransferase indicative of tissue damage
Alanine transferase (ALT): increases in viral hepatitis, liver cell necrosis, prolonged circulatory collapse
Aspartate transferase (AST): increases 6-8 hours after MI, biliary cirrhosis, liver cancer, pancreatitis, mono, alcoholic cirrhosis and strenuous exercise
ALT more specific to liver disease vs AST

40
Q

Metabolism of Gln, His, Arg, Pro and Glu

A

Hyperammonemia: primary cause of neurological disorders
Glutamate vs glutamine —> N trap mechanism
Glutamine synthetase: Glu —> Gln using NH4+ and ATP (N trap via energy consumption)
Glutaminase: acts as a hydrolase to convert Gln to Glu and NH4+
Reversible reactions whose direction will be dependent on N levels

41
Q

Metabolism of Met, Thr, Ile and Leu

A

Methionine pathway —> homocystinuria

Cystathionine beta-synthase needs PLP coenzyme

42
Q

Clinical manifestations in the Met cycle (and also folate cycle since THF is used as a methyl carrier) includes what?

A

Homocystinuria

43
Q

Describe the role of homocysteine methyltransferase enzyme in homocystinuria

A

Defect in this enzyme can cause secondary homocytisinuria
Uses cobalamin/vit B12 as coenzyme and THF as methyl carrier
Converts homocysteine to methionine

44
Q

Describe the role cystathionine beta synthase (CBS) enzyme plays in homocytinuria

A

Converts homocysteine —> cystathionine
Needs PLP as a coenzyme (active form of vitamin B6)
Mutations in this enzyme are the most common cause of homocystinuria

45
Q

Consequences of homocystinuria and homocysteinemia can affect four organ systems including

A

Ocular: ectopia, lentis and high myopia
Skeletal: limbs grow out of proportion with trunk, anterior chest wall deformities, osteoporosis and altered facial appearance
CNS: dementia
Vasculature: stroke and thrombosis

46
Q

What are hyperhomocysteinemia and homocystinuria?

A

Vitamin deficiencies such as B6, B12 and folic acid or genetic defects in enzymes (CBS) respectively that cause defective metabolism of homocysteine

47
Q

Hyperhomocysteinemia is a risk factor for what?

A

Atherosclerotic heart disease and stroke and can result in neuropsychiatric illness (vascular dementia, Alzheimer’s disease)
Also lens dislocation in the eyes, osteoporosis and mental retardation

48
Q

What can normalize plasma homocysteine levels in some cases?

A

Vitamin supplementation (with B vitamins)

49
Q

Describe the metabolism of branched chain amino acids (BCAs)

A

Metabolism produces both ketogenic and glucogenic intermediates
Branched chain alpha keto acid dehydrogenase performs oxidative decarboxylation
Needs CoA, FAD (B2), lipoic acid, NAD (B3) and TPP (B1)

50
Q

Deficiencies in the BCA metabolism pathway lead to what condition?

A

Maple syrup urine disease (MSUD)

51
Q

Describe maple syrup urine disease

A

Rare autosomal diseases resulting from deficient branched chain alpha keto acid dehydrogenase complex (BCKD) activity which results in branched chain ketoaciduria
BCAAs in urine give hallmark maple syrup smell
Also accumulate in blood causing toxic effects on brain function and eventually mental retardation
Tx includes a synthetic diet limiting BCAAs (Val, Leu and Ile)
BCKD activity may be restored with thiamine supplementation

52
Q

Which population presents with higher risk of MSUD?

A

Mennonite, Amish and Jewish populations

53
Q

Asparagine metabolizes to what?

A

Aspartate by the removal of an amine group by asparaginase

54
Q

What is the best known clinical presentation of deficiencies in metabolism of Phe?

A

Phenylketonuria which is a debilitating IEM that is now screened for at birth along with galactosemia and tyrosinemia
Controlled with diet
Caused by majority missense mutation in the catalytic domain of the enzyme that converts Phe to Tyr (phenylalanine hydroxylase)
Recombinant expression showed altered kinetics and decreased stability

55
Q

Describe phenylketonuria (PKU)

A

Caused by defects in the activity of Phe hydroxylase (PAH)
Most common IEM and first one to be screened in newborns
Phe instead converted to phenylpyruvate and then to phenyllactate (causes musty odor in urine) and phenylacetate
Latter two disrupt neurotransmission and block aa transport in the brain as well as myelin formation, resulting in severe impairment in brain function
Dietary limit Phe, protein supplied with synthetic formula supplemented with Tyr

56
Q

Secondary PKU can result from

A 
Tetrahydrobiopterin deficiency (a cofactor for PAH) 
Defects in synthesis of regeneration of BH4
57
Q

Tryptophan derivatives

A

Same THB/DHB cycle in Phe —> tyrosine metabolism
Serotonin is the p-hdyroxylated and decarboxylated form of tryptophan
Makes niacin and melatonin

58
Q

Tyrosine derivatives

A

Thyroglobulin made by follicular thyroid cells (~120 Tyr residues)
T4 = coupling two di-iodotyrosine
T3 = mono-iodotyrosine + di-iodotyrosine
Tyrosine peroxidase oxidizes iodine ions to iodine atoms for addition to tyrosine residues on thyroglobulin
Also makes dopamine —> NE —> Epinephrine and melanin

59
Q

Hypothyroidism =

A

High TSH

Low T4

60
Q

Hyperthyroidism =

A

Low TSH

High T4/T3

61
Q

How are albinism and tyrosinase connected?

A

Albinism is due to severe lack of melanin
Conversion of tyrosine to melanin is blocked due to defects in the enzyme tyrosinase
Of blocking of the transfer of tyrosine in the body
Results in partial or complete absence of pigmentation in the skin, hair and eyes

62
Q

Thyroglobulin and thyroid hormones

A

Thyroglobulin is a protein made by the thyroid and is used to produce T4 and T3
Pts with hyperthyroidism are treated with agents (carbimazole and propylthiouracil) which blocks iodination of thyroglobulin to decrease the production of T4 and T3

63
Q

Ammonia is removed as what?

A

Glu and Gln in the brain by glutamine synthase

As Glu in other tissues

64
Q

How is urea generated?

A

In amino acid metabolic pathways by deamination mechanisms

65
Q

Where is urea produced?

A

Primarily in the liver (kidneys to a lesser extent)
Regulated by NAG
Secreted into the blood then filtered by the kidneys to be excreted in the urine

66
Q

Structure of ammonia

A

2 amino groups (NH2)

1 C=O bond

67
Q

Increased entry of ammonia to the brain is a primary cause of what?

A

Neurologic disorders such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathies, Reye syndrome, several other metabolic disorders and some toxic encephalopathies

68
Q

A blood ammonium concentration of what is associated with coma and convulsions?

A

200umol/L

69
Q

Describe the removal of excess NH4+ from the brain

A

Glutamate dehydrogenase keeps on going and keeps on churning out glutamate to use up the NH4
Which in turn depletes the pool of alpha ketoglutarate and lowers the level of ATP and leads to unconsciousness
AKG —> Glu —> Gln (travels to liver from brain) —> converted back into Glu to make NH4+ which enters the urea cycle and is excreted as urea

70
Q

Describe the removal of NH4+ from muscle

A

Pyruvate from glycolysis is converted to alanine by ALT in the muscle which then travels to the liver
Alanine is deaminated by ALT back into pyruvate which enters gluconeogenesis in the liver
The amino group from alanine is taken up by Glu which undergoes oxidative deamination to produce alpha-KG and NH4+ which is sent to the urea cycle to be excreted in the urine as urea

71
Q

Pyruvate is the alpha keto acid of which amino acid?

A

Alanine

72
Q

What are the two major sources of urea cycle deficiencies?

A

Liver disease and IEM

73
Q

Defects in any of the 6 enzymes that contribute to the urea cycle can result in hyperammonemia including

A

NAG synthase which produces N-acetylglutamate (NAG) form glutamate and acetyl CoA
Lack of NAG enzyme results in excessive accumulation of N in the form of ammonia in the blood —> hyperammonemia
Excess ammonia which is a neurotoxin travels to the CNS through the blood resulting in sx and physical findings of NAG deficiency
Sx include vomiting, refusal to eat, progressive lethargy and coma
Autosomal recessive inheritance

74
Q

What is another example of a defective enzyme in the urea cycle?

A

Ornithine transcarbamoylase
Causes hyperammonemia with orotic aciduria
X linked inheritance

75
Q

Describe ammonia toxicity

A

Excessive ammonia due to disorders in the urea cycle or liver failure can have highly toxic effects on the brain and CNS
NH3 is a toxic agent bc of its ability to permeate membranes
Causes pH imbalance, swelling of astrocytes which leads to cerebral edema and intracranial HTN
Postsynaptic excitatory proteins are inhibited which depresses CNS fxn
Depletion of glutamate results in disruption of its neurotransmitter activity (key reactant in formation of GABA)
Ammonia also causes mito dysfunction

76
Q

Urea cycle and the high protein diet

A

Urea production is increased by a high protein diet and decreased by a high carb diet
Insulin and glucagon play a role in urea production
About 20-30% of urea produced is hydrolyzes in the GI tract by bacterial urease which provides a source of N for gut bacteria (salvage and reuse)
High protein diets enhance this production and hydrolysis

77
Q

THB/BH4 cycle

A

Cofactor for hydroxylase enzymes and important in the metabolism of Phe, the Trp derivative pathway and the Tyr derivative pathway (latter two - biosynthesis of serotonin, melatonin, dopamine, NE and epinephrine)

SFM Exam 2 (25 decks)

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