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Protein Turnover Flashcards

1
Q

Where does Protein Turnover Take place?

A

1) Proteins from diet are hydrolyzed in the digestive tract

2) Proteins within each cell are broken within that cell in a proteasome

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2
Q

Degradation of Amino Acids requires:

A

Excess amino acids are neither stored nor excreted

Degradation:

1) Deamination-removal of amino group which enters the Urea Cycle
2) Conversion of carbon skeleton to Glucose/glycogen by converting to:
- acetyl CoA
- Acetoacetyl CoA
- Pyruvate
- Citric Acid Intermediate

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3
Q

Ubiquitin (Ub)

A

Protein found in all eukaryotes
“Mark of Death” tags protein for proteolysis

The Glycine C-Terminal of Ub covalently attaches to the R group of Lys on the protein

Ub forms polymers called polyubiquitination

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4
Q

Ub attachment to protein requires 3 enzymes before attachment:

A

1) E1 or Ubiquitin-activating enzyme
- activates Ub by Adenylation-attachment to AMP
- E1 subunit displaces AMP and Sulfhydryl binds to the Glycine C-terminal carboxylate forming a thioester bond

2) E2 or Ubiquintin-conjugating enzyme
- activated Ub transferred from Sulfhydryl of E1 to sulfhydryl of E2

3) E3 or Ubiquintin-protein ligase
- catalyzes the transfer of Ub from E2 to target protein
- largest gene family in humans

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5
Q

Structure of Proteasome

A

26S Large Protease Complex attacks ubiquinated proteins

1) Two 19S caps contains AAA class ATPase activity
-ATPase associated with various activities
2) One 20S Catalytic Core
4 Rings of 7 subunits-28 subunits total
-14 alpha (outer rings)-7 isoforms
-14 beta (inner rings)- 7 isoforms

Beta subunits contain the Proteolytic active sites
-Threonine residue acts as nucleophile to attach carbonyl of peptide bond

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6
Q

Action of Proteasome

-Function

A

Hydrolyzes Ubiquinated Proteins

Digest proteins to 7-9 amino acid peptides, which are released from proteasome and further degraded to amino acids by cellular proteases

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7
Q

Bortizomib

A

or Velcade
Inhibitor of Proteasome
-Therapy for multiple myeloma

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8
Q

What is the primary site of amino acid degradation?(removal of nitrogen)

A

Liver

-muscle is secondary site of amino acid degradation for branched chain aliphatic amino acids (L, I, V)

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9
Q

Nitrogen Removal from Amino Acids requires what enzymes?

A

Aminotransferase (AKA transaminases)

Glutamate dehydrogenase

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10
Q

Aminotransferase

A

AKA transaminases

-alpha amino group transfered to alpha ketogluterate to form glutamate
Ex: Aspartate Aminotransferase, Alanine Aminotransferase
-Reversible
-also used in synthesis of amino acids
-Prosthetic Group=PLP-pyridoxal Phosphate (Vit B6)

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11
Q

Glutamate Dehydrogenase

A

Converts nitrogen of glutamate to ketone to form alpha ketoglutarate and releases ammonium ion

  • localized to the mt of liver
  • Either uses NAD+ (Degradation) and NADP+(synthesizing)

Close to equilibrium in liver
-Direction of reaction depends on Substrate or Products concentration, but normally, driven forward by removal of Ammonium

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12
Q

PLP

A 
Pyridoxal Phosphate (PLP)
-prosthetic group

Function: Group transfer to or from amino acid
-electron acceptor/donor

Vit precursor=Vit B6-pyridoxine

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13
Q

Serine and Threonine degradation

A 
Directly deaminated (Self deamination)
-Amino group is not transferred to alpha keto glutarate

1) Serine dehydratase
- dehydrates and deaminates serine to produce pyruvate and ammonium

2) Threonine Dehydratase
- dehydrates and deaminated threonine to produce alpha-ketobutyrate and Ammonium

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14
Q

What are we going to do when the amino groups are released from muscles?

A

Peripheral tissues transport Nitrogen to the liver Glucose-Alanine Cycle

1) Muscles use branched amino acids as fuel and amino group is transferred through glutamate to alanine
2) Alanine with the amino group enters the blood and is transported to the liver
2) Once in the liver, transfers amino group to alpha ketoglutarate to form glutamate-> NH4+ through urea cycle
- Alanine is converted to pyruvate for gluconeogenesis to produce glucose

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15
Q

Urea Cycle

A

Cycle responsible for synthesis of urea
-Urea=form of nitrogen excreted in vertebrates

Carbamoyl Phosphate

  • intermediate in urea cycle
  • synthesized from NH3 and HCO-(Bicarbonate derived from hydration of CO2)
  • Carbamoyl Group has a high phosphate transfer potential due to anhydride bond
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16
Q

How much urea does Human excrete per year?

A

10Kg=22lbs

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17
Q

Source of Atoms in Urea?

A

1 N from free ammonium (NH4+)
C from HCO3- (bicarbonate derived from hydration of CO2)
1 N from Aspartate

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18
Q

Carbamoyl Phosphate Synthetase

-reaction

A

Catalyzes the 3 Step synthesis of Carbamoyl Phosphate

  • matrix of mitochondria
  • uses 2 ATP to synthesize Carbamoyl Phosphate
  • carbamoyl phosphate has a high phosphate transfer potential due to anhydride bond

1) Bicarbonate (HCO3-) phosphorylated by Phosphate from ATP forming Carboxyphosphate
2) Carboxyphosphate reacts with ammonia to form carbamic acid
3) Carbamic acid is phosphorylated by ATP to yield Carbamoyl Phosphate

Isozyme catalyzes the synthesis of carbamoyl phosphate for use in pyrimidine synthesis

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19
Q

Carbamoyl Phosphate Synthetase

-structure

A

1)Three Reaction sites
-Glutamine hydrolysis site
-Bicarbonate Phosphorylation site
-Carbamic Acid phosphorylation site
2) Substrate Channeling
-Substrate passed through channel from one active site to the next active site without releasing the enzyme
Benefits?
-increases rate of reaction
-protects libile substrates from degradation by hydrolysis

20
Q

Ornithine Transcarbamoylase

A

Carbamoyl Phosphate + Ornithine-> Citrulline

  • occurs in mt matrix
  • following synthesis citrulline is transported to the cytoplasm
21
Q

Arininosuccinate Synthetase

A

Citrulline + Aspartate-> Argininosuccinate

  • condensation reaction at the expense of ATP which is hydrolyzed to AMP + PPi
  • occurs in the cytoplasm
22
Q

Arginosuccinase

A

Cleaves Argininosuccinate-> Arginine + Fumurate

  • conserves carbon skeleton of aspartate in fumurate
  • occurs in cytoplasm
23
Q

Arginase

A

Arginine-> Ornithine + Urea

  • Ornithine transported into mitochondria
  • Urea excretes
24
Q

What links Urea Cycle to Gluconeogenesis?

A

Aspartate and Fumarate

25
Ketogenic Amino Acids
Carbon skeletons are converted into intermediated (Acetyl CoA or Acetoacetyl CoA) that can form ketone bodies or Fatty Acids -NOT substrates for Gluconeogenesis
26
Glucogenic Amino Acids Definition
Carbon Skeletons are converted into intermediates that can be used to synthesize glucose
27
What are the the intermediates that the Carbon Skeletons from deaminated Amino Acids are converted into?
7 - Pyruvate - Acetyl CoA (KETOGENIC) - AcetoAcetyl CoA (keotgenic) - a-ketoglutarate - Succinyl CoA - Fumurate - Oxaloacetate
28
Overview Mech of Urea Cycle:
1) Carbamoyl Phosphate + Ornithine (mt)-> Citrulline 2) Citrulline + Asparate-> Argininosuccinate 3) Arginino Succinate -> Fumurate + Arginine 4) Arginine + H2O -> Ornithine + Urea
29
Whats required for degradation of Aromatic Amino Acids
Oxygenase! Phenylalanine Hydroxylase (Monooxygenase) - Hydroxylates Phe-> Tyr - Tetrahydrobiopertin=electron carrier
30
What are the 2 types of Oxygenases?
Monooxygenase -each atom of O2 is incorporated into 2 different products Dioxygenase -both atoms of O2 are incorporated into single product
31
Tetrahydrobiopertin (BH4)
electron carrier derived from Biopertin Synthesized in vivo from phenylalanine, not a vitamin bc it is synthesized in the body 1) Phenylalanine hydroxylase - synthesized dihydrobiopertin by hydroxylating phenylalanine which forms Tyrsoine 2) Dihydrofolate reductase - reduces dihydrobiopertin to tetrahydrobiopertin using NADPH 3) Dihydropteridine reductase - reduces quinoid dihydrobiopertin using NADPH
32
Mechanism to breakdown Phe
1) Phe-> Tyr by deamination using Phenylalanine Hydroxylase with Tetrahydrobiopertin 2) Transamination--Tyrosine amino transferase Tyr-> P-hydroxyphenylpyruvate 3) P-hydroxyphenylpyruvate hydroxylase - Dioxygenase-both oxygen atoms incorporated to Product - Homogensitate 3) Homogentisate oxidase (dioxygenase) 4) Isomerization 5) Hydrolyzed - Fumarate + Acetoacetate (reason why they are both glucogenic and ketogenic)
33
Trp degradation mechanism
converted into alanine and Aspartate via the action of several oxidases 1)Dioxygenase, 2) NH3+ 3) Monoxygenase,4)alanine released 5) dioxygenase 6)Acetoacetate x11 steps
34
Amino Acids -> Alpha Ketogluterate
Gln-> Glu via Glutaminase Glu deaminanted pinot Alpha Ketogluterate via Glutamate dehydrogenase NAD+ Arg-> Ornithine-> Gluatamate Y semialdehyde -> Glutamate Pro -> Glutamate Y semiadlehdye-> Glutamate His: multistep process with 4-imidazolon 5-Propionate intermediate-> Glutamate
35
Amino Acids-> Succinyl CoA
Val/ Isoleucine-> Propionyl CoA-> Methylmalonyl CoA-> Succinyl CoA Methionine-> SAM->S-adenosylhomocysteine-> Homocysteine + Serine(R group attaches and loses O bond to S)->Cystathionine-> release of cysteine + a-ketobutyrate-> Propinoyl CoA--->>>>>>Sucicinyl CoA
36
Amino Acids-OAA
Asp -direact deamination into OAA Asn: -NH4+ removed via Asparaginase to form Asp
37
Degradation of cellular proteins
Proteins turnover within the cell - Damaged/misfolded are identified by Ub and destroyed quickly - Proteins that are no longer needed Half life of proteins vary from protein to protein Deteremine by N-terminal residue -R or L favors ubiquination=fast destruction -M or P disfavors ubiuination=slow destruction/long half life
38
Excretion of Nitrogen: | -different species
Terrestrial vertebrates -Ureotelic-excrete excess nitrogen as urea Aquatic vertebrates and invertebrates -ammoniotelic-excrete excess nitrogen as ammonium Birds and reptiles -Uricotelic-excrete excess nitrogen as uric acid
39
Tetrohydrobiopertin
BH4 -electron carrier -synthesized in vivo from phenylalanine, not a vitamin because it is synthesized in the body Phenylalanine hydroxylase-synthesizes Dihydrobiopertin by hydroxylating phenylalanine dihydrobiopterin reductase -reduces dihydrobiopterin to tetrahydropterin Dihydropteriteridine reductase -reduces quinoiod dihydrobiopterin to tetrahydropterin
40
Degradation of Dietary Proteins
Begins in stomach: -ph=2, acidic environment allows the primary proteolytic enzyme, nonspecific, pepsin to function at maximum activity -breaksdown proteins to Oligopeptides and amino acids and head to the lumen of intestine lumen of intetine - Most enzymes involved in digestion are synthesized in the pancreas and secreted as Zymogens - Aminopeptidase-nonspeicfic protease in the intestinal wall of cell that sequentially hydrolyzes proteins from the amino terminal end - then amino acids enter blood stream
41
Hyperammonemia
inherited disease of urea cycle -elevate levels of ammonium (NH4+) in blood causes include: - lack/reduced synthesis of carbamoyl phosphate - lack/reduced activity of the four enzyme of urea synthesis
42
Treatments of Hyepammonemias
1) Argininosuccinase deficiency - Provide excess arginine in diet - restrict Total protein in diet which reduces the amount of nitrogen to be excreted Xs supply of arginine is converted to ornithine which reacts with carbamoyl phosphate to form citrulline which reacts with aspirate to formargininosuccine which is excreted 2) Carbamoyl Phosphate synthetase or Ornithine transcarbamoylase deficiency treatment - excess nitrogen accumulates in glycine and glutamine - restrict protein in diet
43
Alcaptonuria
First description of an inborn error of metabolism Defective degration of Phe to Tyr - recessive inheritance - homogentisate accumulates and is excreted in the urine as a highly colored polymer - harmless condition
44
Maple Syrup Urine Disease
Branched-chain Ketoaciduria Defective/missing branched-chain dehydrogenase Defective degradation of Ile, Valine, Leucine -causes mental and physical retardaiton -detected by mass spec
45
PKU
Phenylketonuria defective/missing phenylalanine hydroxylase(or the tetrahydrobiopterin cofactor) -Autosomal recessive -Untreated PKU can caused reduced life expectancy 20s-30s and retardation

MC Biochem 2 (31 decks)

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