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FoundSci Unit 4 > Protein III & IV > Flashcards

Protein III & IV Flashcards

1
Q

Explain amino acid degradation during the fed state

A

Insulin stimulates glucose utilization

Amino acids released in circulation after eating dietary protein travel via the hepatic portal system to the liver

In liver, amino acids are used to make proteins, mainly albumin

Amino acids that pass through liver enter amino acid pool and become available to other tissues for protein synthesis

Excess amino acids are deaminated and carbons skeletons are turned into intermediates of glycolytic pathway, TCA cycle, and lipid metabolism

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2
Q

Explain amino acid degradation during fasting state

A

Insulin secretion is low while glucagon secretion increases in response to low blood glucose

Liver responds with increased gluconeogenesis

Skeletal muscles respond to low blood glucose by providing substrates for liver gluconeogenesis such as amino acids and lactate

Amino acid catabolism begin with removal of amino groups and resulting carbon skeletons are converted into glucose or ketone bodies, which can be used for energy generation

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3
Q

What is important about alanine and glutamine?

A

Two most common non-toxic transport forms of ammonium ions

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4
Q

Explain alanine trafficking

A

Alanine traffics to the liver only where it is converted back to pyruvate by ALT and ammonium ions enter urea cycle

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5
Q

Explain glutamine trafficking

A

Glutamine traffics to the liver, kidney, and intestines

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6
Q

What happens to glutamine trafficked to kidney?

A

In kidney, glutaminase converts glutamine to glutamate and ammonium ions are released in the urine

Glutamate can then be converted to alpha-ketoglutarate and enter TCA cycle

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7
Q

What happens to glutamine trafficked to liver?

A

Glutamine converted to glutamate via glutaminase while ammonium ions enter urea cycle

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8
Q

What happens to glutamine trafficked to intestines?

A

Glutamine is converted into ammonium ions and glutamate by glutaminase

Glutamate can form alpha-ketoglutarate that can enter the TCA cycle

Glutamate can also be converted into ornithine, which then forms citrulline

Ammonium ions transported to liver where they enter urea cycle

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9
Q

Glucogenic Amino Acids

A

Majority of amino acids except lysine and leucine

Intermediate/Products - alpha-ketoglutarate, oxaloacetate, succinyl-CoA, fumarate, and pyruvate

Product - Glucose via liver gluconeogenesis

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10
Q

Ketogenic Amino Acids

A

Leucine and Lysine

Intermediates/Products - Acetyl-CoA and acetoacetate

Product - Ketone bodies

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11
Q

What is the function of glutamate dehydrogenase?

A

Major player in amino acids degradation during fasting/starvation

Acts mainly in the liver

Oxidizes glutamate to alpha-ketoglutarate, NADH, and ammonium

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12
Q

How is glutamate dehydrogenase regulated?

A

High levels of GTP and NADH inhibit the enzyme - high cellular energy charge

High levels of ADP activate the enzyme (low cell energy charge)

Most active under fasting or stress where requirement for energy generation through amino acid oxidation is needed

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13
Q

What do aminotransferases and mitochondrial glutamate dehydrogenase together do?

A

Act together to direct alpha-ketoacids towards energy yielding metabolism while funneling ammonia into urea cycle

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14
Q

Familial Hyperinsulinemic Hypoglycemia Type 6 (HHF6)

A

Cause - Mutation to GLUD1 gene that encodes GDH so GDH is insensitive to GTP inhibiton

Symptoms: Appear during high protein diet. Hyperammonemia due to elevated ammonia levels and hypoglycemia due to increased ATP which promotes insulin release

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15
Q

How is glycine degraded?

A

By the glycine cleavage system.

GCS is located in mitochondria and is reversible

Requires THF and N5,N10-methylene THF.

Glycine can be converted back to serine by SHMT (serine hydroxymethyltransferase)

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16
Q

Patient presents with elevated glycine, seizures, lethargy, and lack of muscle tone (hypotonia). What is the patient’s condition?

A

Glycine Encephalopathy

Caused by mutations in genes associated with glycine cleavage system.

Known as nonketotic hyperglycemia

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17
Q

How is propionyl-CoA degraded?

A

Propionyl-CoA is common intermediate in catabolism of isoleucine, threonine, methionine, and valine.

Propionyl carboxylase carboxylates propionyl-CoA to D-methymalonyl-CoA in reaction that requires ATP, CO2, and biotin as cofactor

Racemase isomerizes D-methylmalonyl-CoA to L-methylmalonyl-CoA

Mutase convertes L-methylmalonyl-CoA to succinyl-CoA and requires Vitamin B12 as cofactor

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18
Q

Propionic acidemia

A

Loss of propionyl-CoA carboxylase

Causes accumulation of propionic acid and metabolic acidosis

Symptoms include metabolic acidosis, vomiting, rapid breathing, and lethargy

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19
Q

Methylmalonic aciduria

A

Defect in mutase or deficiency in vitamin B12 results in accumulation of methylmalonate in serum and urine

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20
Q

What is important about the homocysteine-methionine cycle?

A

Contributes to methyl conjugation of drugs, hormones, neurotransmitters, DNA, RNA, and proteins

Allows homocysteine to be converted into methionine and cysteine

Reaction catalyzed by methionine synthase - requires Vitamin B12

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21
Q

What is important about methionine synthase?

A

Converts homocysteine to methionine.

Has absolute requirement for Vitamin B12

Only reaction in mammals that coverts N5-methyl THF back to THF

22
Q

How is vitamin B12 absorbed?

A

Vitamin B12 is released from food in the stomach

In the ileum, the intrinsic factor binds vitamin B12 and helps its absorption

In the blood, transcobalamin transports vitamin B12 to tissues

22
Q

What are the sources of Vitamin B12?

A

Bacteria are the only source. Vitamin B12 can be found in animal products from ruminants and shellfish

23
Q

Vitamin B12 deficiencies

A

Actual B12 deficiency - lack of vitamin B12 in diet, usually with vegans

Functional B12 deficiency - Inability to absorb or metabolize vitamin B12

Pernicious Anemia - severe lack of intrinsic factor due to gastric atrophy , cause can be organ specific autoimmune. Presence of antibodies against the intrinsic factor present

24
Q

What is the biochemical basis of Vitamin B12 deficiency?

A

Non-functional methionine synthase

Non-functional mutase reaction

25
Q

What occurs with non-functional methionine synthase?

A

Causes trapping of THF as N5-methyl THF

Decrease in N5, N10 methylene THF -> Blockage in DNA replication

Folate can restore purine and thymidine synthesis, but cannot prevent homocysteine accumulation

26
Q

What occurs with non-functional mutase reaction?

A

Accumulation of methylmalonate and malonate

Folate cannot prevent methylmalonate accumulation

27
Q

What are the clinical features of Vitamin B12 deficiency?

A

Megaloblastic anemia - large, immature, homeglobin poor red blood cells because of impairment of DNA synthesis in bone marrow cells

Demyelination - damage to myelin sheath of neuron

Artherosclerosis - high homocysteine due to deficiency of Vitamin B12

Methylmalonic aciduria (methylmalonic acidemia)

Diagnostic metabolites: methylmalonyl-CoA, methylmalonate and homocysteine

28
Q

How are branched chain amino acids degraded? What are the branched chain amino acids?

A

Leucine, Isoleucine, Valine

BCAAs bypass the liver and enter muscle where they are degraded by muscle branched-chain aminotransferase (BCAT) (requires PLP) - produces branched chain alpha-ketoacids

The branched chain ketoacids travel to the liver where they are oxidatively and irreversibly decarboxylated by branched chain alpha-ketoacid dehydrogenase (BCKDH) - produces branched chain acyl-CoAs

29
Q

What product is formed from leucine degradation in the liver?

A

Acetyl-CoA and acetoacetate

30
Q

What product is formed from isoleucine degradation in the liver?

A

Propionyl-CoA and acetyl-CoA (glucogenic and ketogenic)

31
Q

What product is formed from degradation of valine in liver?

A

Propionyl-CoA (glucogenic)

32
Q

Maple Syrup Urine Disease

A

Impaired activity of branched chain keto acid dehydrogenase (BCKDH), which results in accumulation of branched chain alpha-keto acids and increased serum levels of branched chain amino acids.

Symptoms include maple syrup odor to urine and brain edema.

Diagnostic metabolites - High BCAAs in blood and high BCKAs in urine

33
Q

Inborn error in tyrosine degradation pathway. Patient presents with keratitis and photophobia.

A

Tyrosinemia II

Loss of tyrosine aminotransferase enzyme

34
Q

Alkaptonuria

A

Inborn error in tyrosine degradation pathway.

Loss of homogentisate oxidase which results

Diagnostic metabolites - Homogentisate and alkaptone

Symptoms are black urine and joint destruction

Treat with nitisone which inhibits production of homogentisate

35
Q

Inborn error in tyrosine degradation. Loss of fumarylacetoacetate hydrolase

A

Tyrosinemia I

Diagnostic metabolites: succinylacetone

36
Q

What are the sources of ammonium ions?

A
  1. Aminotransferase reactions
  2. Deamination (serine, cysteine, histidine, and threonine)
  3. Purine and pyrimidine metabolism
37
Q

How are ammonium ions used in the body?

A
  1. Synthesis of glutamine
  2. Synthesis of urea
  3. Excretion in urine as NH4+
38
Q

What are the signs of ammonia toxicity?

A

Neurological effects

Brain swelling

Lethargy, stupor, vomiting, and convulsions

39
Q

What organ converts ammonium ions to urea?

A

Liver

40
Q

Where did the two nitrogens in urea originate from?

A
  1. Ammonia
  2. Alpha-amino group of aspartate
41
Q

What are the basic steps of the urea cycle?

A
  1. Carbamoyl Phosphate Synthetase Reaction in mitochondria
  2. Ornithine Transcarbamylase Reaction in mitochondria
  3. Argininosuccinate Synthetase reaction in cytoplasm
  4. Argininosuccine Lyase Reaction in cytoplasm
  5. Arginase Reaction in cytoplasm
42
Q

What occurs during the first step of the urea cycle with Carbamoyl Phosphate Synthetase?

A

Rate limiting step of urea synthesis

Carbamoyl phosphate synthetase, activated by N-acetylglutamine, converts ammonium into carbamoyl phosphate

43
Q

What occurs during step 2 of urea synthesis with ornithine transcaramylase?

A

Ornithine transcarbamylase converts carbamoyl phosphate and ornithine to citrulline

44
Q

What occurs during step 3 of urea synthesis with argininosuccinate synthetase?

A

Citrulline and aspartate are converts to argininosuccinate through the enzyme argininiosuccinate synthetase

45
Q

What occurs during step 4 of urea synthesis with the enzyme argininosuccinate lyase?

A

Argininosuccinate is converted to arginine and fumarate via argininosuccinate lyase

46
Q

What occurs in the last step of urea synthesis with the enzyme arginase?

A

Arginine is converted to ornithine and urea via arginase

47
Q

How do different tissues participate in the urea cycle?

A

Small intestine - epithelial cells produce citrulline from glutamine

Kidney - Once in kidney, citrulline is converted into arginine and arginine is released in the blood. Referred to as intestinal-renal axis.

Liver is only organ that can do entire urea cycle

48
Q

What are early step urea cycle enzyme deficiencies?

A

Deficiency in either carbamoyl phosphate synthetase I or ornithine transcarbamoylase

Results in severe hyperammonemia and is lethal

49
Q

What are late step urea cycle enzyme deficiencies?

A

Less toxic since intermediates are less toxic than ammonium

Examples:
Citrullinemia - Loss of argininosuccinate synthetase. Diagnostic metabolite is citrulline

Argininosuccinic aciduria - loss of argininosuccinate lyase. Diagnostic metabolite is argininosuccinate

Hyperargininemia - Loss of arginase. Diagnostic metabolite is arginine

50
Q

What are the treatment options for early cycle enzyme defects of urea cycle disorders?

A

Protein restriction - very severe

Removal of ammonium ions independent of urea formation - form water soluble conjugates with glutamine and glycine

51
Q

What are the treatment options for late cycle enzyme defects of urea cycle disorders?

A

Removal of ammonium ions independent of urea formation - form water soluble conjugates with glutamine and glycine

Dietary intervention - supplement diet with high doses of arginine

FoundSci Unit 4 (11 decks)

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