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P1 Spring 2024 > biochem - amino acid oxidation > Flashcards

biochem - amino acid oxidation Flashcards

1
Q

Amino Acid Catabolism: Some Thoughts

A

Amino acids have a “toxic” part, and an energetic part. Biology must deal with both, and efficiently.

In general:
1. The amino group is removed from each AA and metabolized to a form that can be excreted (urea) - nitrogen needs to be excreted as urine
2. The carbon skeleton is metabolized separately

process:
1. intracellular protein

  1. break down into amino acids
    - each amino acid gets split into an amino group (which is kinda toxic) and carbon skeletons (for energy)

amino group
- can go into the biosynthesis of amino acids, nucleotides, and biological amines
- can also be made into carbamoyl phosphate to go into the urea cycle and the nitrogen will leave as urea which is the nitrogen excretion product - pee

carbon skeletons
- can be made into alpha-keto acids or pyruvate, acetyl-CoA, acetoacetyl-CoA, alpha-ketoglutarate
- can go into the CAC and let out CO2, H2O & ATP
- can let out oxaloacetate which is useful or the anabolism of many things
- then will finally be released as glucose (synthesized in gluconeogenesis)

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2
Q

Outline of Amino Acid Catabolism

A
  1. Digestion of Amino Acids (after intracellular protein)
    1. Amino Acid Catabolism:
      Toxic Ammonia: Amino-transfer Reactions
  • Transamination→Deamination
    1. Nitrogen→Carbamoyl Phosphate
    1. Carbamoyl Phosphate→Urea Cycle
    1. Carbon Skeleton Catabolism
  • Pyruvate, Acetyl-CoA, Acetoacetyl-CoA,
    α-ketoglutarate, Succinyl-CoA, Oxaloacetate * Where do these go?!
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3
Q

excretion of N-compounds

A

most aquatic species (ammonotelic) excrete nitrogen as ammonia (the dilution solution). Quickly diluted; aquatic

birds and reptiles (uricotelic) excrete amino nitrogen as uric acid. Less toxic than ammonia; no H20, little energy

most other terrestrial animals - including humans - (ureotellic) excrete urea (the detox solution)

urea cycle requires ATP & H2O

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4
Q

How do we get our Amino Acids?: Diet/Digestion

A

Animals are most likely to get energy from the catabolism of amino acids under the following conditions:

  1. Digestion of AA’s as part of the normal catabolic/anabolic degradation/formation process
  2. When the diet is too rich in proteins - AA’s can’t be stored.
  3. During starvation,or untreated diabetes (carbs not available or improperly utilized)
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5
Q

Quick Note on Physiology

A

Zymogens (inactive) to active proteases

clip off the “ogen” to be active!

stomach (gastric glands)
- has pepsinogen

stomach
- pepsin

pancreas
- trypsinogen
- chymotrypsinogen
- procarboxypeptidases

small intestines
- trypsin
- chymotrypsin
- carboxypeptidases

small intestine brush border
- other peptidase zymogens

small intestine
- amino and carboxypeptidases

acute pancreatitis
- if secreted zymogens cannot enter the intestine
- they are activated prematurely in the pancreas
- they begin to attack pancreatic tissue
- painful, harmful, and sometimes fatal

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6
Q

Amino Acid Digestion

A

stomach - Pepsin protein
- gastric juice (pH 1.0-2.5)
- kills bacteria
- unfolds proteins
- pepsin begins to cleave proteins

small intestine (pancreas)
- oligopeptides: trypsin & chymotrypsin

pancreas makes and excretes zymogens (inactive)
zymogens are activated in the small intestine
- oligopeptides: carboxypeptidases
- aminopeptidases

intestinal epithelial cells to blood capillaries to liver

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7
Q

Amino Transfer Reactions
but NH4+ is toxic, how do we get rid of it?

A

Ammonia is toxic – we can’t just let it float around our physiology being…toxic.

So what do we do?
Transamination → Deamination

We put that ammonia as an amino group onto a carbon skeleton and let that carbon skeleton transfer the ammonia around.

It’s not free, it’s not toxic.

The liver then deaminates and that ammonia goes to the urea cycle for excretion as urine

intestinal epithelial cells to blood capillaries to liver

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8
Q

Amino Transfer Reactions: Trans/Deamination in General: Step 1

A

This happens in the liver…

  1. Almost any AA reacts with α-KG (intermediate from the CAC, too) to form glutamate and an α-keto acid (transamination)
  2. Pretty easy reaction. Reversible.

rxn:
1. α-ketoglutarate + L-glutamate (an amino acid, can be with any amino acid)
- uses: pyridoxal phosphate: a cofactor for all aminotransferases (coenzyme form of vitamin B6)

  1. Result: L-amino acid + α-keto acid
    - uses aminotransferase
    the α-ketoglutarate becomes L-amino acid and L-glutamate becomes α-keto acid

delta G = 0

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9
Q

Amino Transfer Reactions: Trans/Deamination in General: Step 2

A

This happens in the liver…
4. Then, glutamate is oxidized with
the help of NAD+…

  1. And then, with the help of H2O, NH4+ is released to the Urea Cycle (deamination)
  2. And α-ketoglutarate is reformed to participate in another transamination, gluconeogenesis, or the CAC
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10
Q

Amino Transfer Reactions: Trans/Deamination: Extrahepatic Tissue

A

Other tissues must metabolize amino acids as well.

Ammonia is toxic, and it must get to the liver. How? - Glutamine

Glutamine is a non-toxic transporter of ammonia in the blood to get ammonia to the liver for transamination

In fact, in the blood, it is the most abundant free amino acid

  1. In extrahepatic tissue, glutamate receives a phosphate (from ATP) and an ammonia (from an amino acid) to form glutamine (transamination)
    - “mine” for the amine that it gets from the amino acid
  2. Glutamine transports that toxic ammonia through the blood and into the liver
  3. Ammonia is released to the urea cycle. Glutamate is formed and can be deaminated to form →α-KG
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11
Q

Amino Transfer Reactions: Trans/Deamination: Muscle

A

glucose-alanine cycle:

muscle metabolizes glucose and AA’s forming pyruvate + NH4+ = alanine, which is transported to the liver; the liver uses ATP energy to make glucose for transport to the muscle

NH4+ + Glutamate + Pyruvate → Alanine + α-KG
Alanine → Blood
Alanine @ Liver Reverse of transamination of extrahepatic tissue

muscle
amino acid to NH4+ to glutamate

  1. glucose in glycolysis turns into pyruvate
  2. glutamate + pyruvate + alanine aminotransferase = alanine + α-KG
  3. NH4+ on alanine goes into the blood
  4. then to the liver
  5. α-KG + alanine + alanine aminotransferase = pyruvate + glutamate + NH4+ which can leave the liver to go into the urea cycle
  6. pyruvate goes into gluconeogenesis = glucose
  7. glucose leaves the liver to go into the blood as blood glucose
  8. glucose goes back into the muscle to repeat back at step 1
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12
Q

Clinical Connections

A

aspartate aminotransferase (AST) is found in many human tissues and spills out when cells are damaged

a common assay measures the serum conc. of AST. An elevated level may indicate liver disease, skeletal muscular disease, myocardial infarction, or other disease

a comprehensive metabolic panel often includes an assay to measure the serum conc. of alanine aminotransferase (ALT)

the ALT assay is used primarily to check for hepatic (liver) disorders

kidneys can also metabolize glutamine
- in metabolic acidosis, the kidneys extract a greater fraction of blood gln. then…
- NH4+ is released from the gln and some of it is combined with anions to form salts which can then be excreted in the urine
- in the CAC, alpha-ketoglutarate is decarboxylated releasing CO2 which an form bicarbonate which buffers the blood raising the pH

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13
Q

We Have Transported our NH4+ to the Liver!

Now What? Well, NH + + HCO - + ATP→ Carbamoyl Phosphate!

A

Urea cycle begins in the mitochondria

oxaloacetate is from the CAC

Notes:
1. This reaction leads up to the Urea cycle

  1. The sources of the ammonia come from various places but converge on glutamate
  2. Trans/Deamination (previously)
  3. NH + + HCO - + 2 ATP→ 43
    Carbamoyl Phosphate *Regulated!
  4. Oxaloacetate + NH4+ → aspartate (transamination; for next slide)

Why aspartate? This pathway is a good way to put amino groups on carbon skeletons (anabolism)

And: ASP→OA→malate→OA makes NAD/NADH for the CAC! (Krebs Bicycle Slide)

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14
Q

Now: Urea Cycle: Carbamoyl Phosphate→Urea

A

Notes:

Previous Slide
1. Urea has 2 amino groups – 1 from amino acid, the other from aspartate

  1. Mitochondrion and Cytosol
  2. 4 Steps
  3. C.P → Citrulline
  4. Citrulline → Arginiosuccinate
    through aspartate (other amino group). ATP→AMP + Ppi
  5. Arginiosuccinate → Arginine + Fumarate
  6. Arginine → ornithine and we MAKE UREA
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15
Q

Urea Cycle + CAC = “Krebs Bicycle”

A

Notes:
1. The Urea Cycle and the CAC are connected!

  1. Aspartate enters the urea cycle from oxaloacetate from the CAC
  2. Fumarate leaves the Urea cycle, gets converted to malate, and enters the CAC.
  3. Malate → oxaloacetate generates NADH!
  4. The CAC must work well for the Urea Cycle to work as it provides the aspartate and removes the fumarate!
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16
Q

Urea Cycle Input/Output “Balance Sheet”

A

it requires energy to synthesize urea and get rid of it

use ATP to make urea

17
Q

Net Urea Cycle Equation:

A

Net Urea Cycle Equation: 2 Glutamate + CO2 + O2 + 2 ADP + 2 Pi→2 α-ketoglutarate + urea + 3 H2O + 2 ATP

18
Q

Regulation of AA Catabolism

A

Notes:
1. Long Term Regulation:
When the diet is high in protein, cells make more urea cycle enzymes.
When the diet is low in protein, cells decrease the concentration of urea cycle enzymes.
- regulation of synthesis of all U.C enzymes

  1. Short Term Regulation:
    When the diet is high in protein, arginine (an amino acid) allosterically stimulates the enzyme responsible for the formation of carbamoyl phosphate
    →speeds up catabolism.
    - allosteric regulation

HCO3+ + NH4+ + carbamoyl phosphate synthetase I makes carbamoyl phosphate

19
Q

health problems and solutions

A

genetic defects in UC enzymes reduce the ability to digest protein-rich foods

amino acids and NH3 accumulate

solution: restrict AA (protein) intake; but cannot completely omit from diet (essential)

20
Q

Quick Summary

A
  1. Digestion of Amino Acids
    1. Amino Acid Catabolism: Toxic Ammonia: Amino-transfer Reactions
  • Transamination→Deamination
  • 3.Ammonia→CarbamoylPhosphate
    1. Carbamoyl Phosphate→Urea Cycle
21
Q

Carbon Skeleton Catabolism

A

Theaminogroupiscatabolized
through the Urea Cycle

  • The carbon skeleton of each molecule is catabolized in a unique way (yay enzymes!)
  • These pathways funnel into just 5 different intermediates of the CAC
  • Convergent Catabolism
  • Not every AA that enters a cell is fully
    broken down to CO2
  • Some are broken down into intermediates (catabolism) and then built into larger molecules (anabolism)
  • Usually → ketone bodies (Ketogenic)
  • Or→glucose/glycogen(Glucogenic)

ketogenic: lysine & leucine

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

ketogenic: Lys, Leu

both gluco and ketogenic: Tyr, Phe, Thr, Iso, Trp,

22
Q

Introducing some new cofactors…

A

key cofactors in AA metabolism

PLP: for transamination

biotin: for C-transfer as CO2 (HCO3) (Pyr to OA)

Tetrahydrofolate: for CH2OH, CHO, & occasionally CH3 - vitamin B9

S-adenosylmethionine: for CH3

tetrahydrobiopterin: oxidation rxns (Phe)

cofactors:
TPP = thiamine pyrophosphate from thiamine

FAD - from riboflavin

Coenzyme A (CoA, from pantothenate)

NAD - from niacin

Lipoate

23
Q

Folate & THF

A

folate is a B vitamin

THF is a cofactor

24
Q

What about THF?

A
  • used to make new cells
  • DNA & RNA synthesis
  • preventing changes to DNA
  • preventing cancer
  • esp important for periods of rapid cell division and growth such as infancy and pregnancy
  • reduces risk of neural tube defects ex: spinal bifida

What happens if we don’t have it?
- accumulation of homocysteine to risk factor for heart disease and stroke
- among other things, B12 or folate deficiency slows DNA synthesis, inhibiting the production of mature erythrocytes (megaloblastic anemia - very large RBCs)

therapy: administration of B12 and or folate
- careful: if the deficiency is in b12 and only folate is administered the catabolism of an odd number of fatty acids may still be blocked, resulting in FA accumulation in neuronal membranes and or synthesis of faulty membranes - nerve damage

B9 & B12 intersect for the synthesis of DNA

25
Q

catabolism

A

to pyruvate: threonine to pyruvate

catabolism of 5-carbon AA’s to alpha ketoG: arginine to alpha ketoG

metabolism of 4 carbon straight chain AA’s to oxaloacetate: Asn to oxaloacetate

catabolism of succinyl-CoA - methionine to succinyl-CoA

26
Q

catabolism of branched-chain AA’s

A

Notes:
Val, Ile, Leu are the only amino acids that are catabolized (in part) outside of the liver.

Branched-chain α-keto acid dehydrogenase complex:

is the same 3, 5, 2 system that we saw with the pyruvate dehydrogenase complex (lead-in to the citric acid cycle: pyruvate→ acetyl-CoA)

and the α-ketoglutarate dehydrogenase complex (Step 4 of the CAC: α-KG→Succinyl-CoA)

Maple Syrup Urine Disease:
defect in BCKAD (above). Autosomal recessive
What does it lead to a buildup of? What does it smell like?
How do we control it?

27
Q

catabolism to acetyl-CoA

A

Trp to acetyl-CoA

28
Q

another possible fate of Trp

A

trp to serotonin, niacin, indolacetate

29
Q

Phe and Tyr cat.

A

Phe to Tyr homogentisate

Tyr is dopamine and catecoline

homogentisate to acetoacetyl-CoA

30
Q

Phenylketonuria (PKU)

A

Results from a defective enzyme: phenylalanine hydroxylase (PAH)

  • Most common genetic disorder affecting AA metabolism (< 8/100,000). Screening available
  • Accumulation of Phe leads to defective neural tube development and brain development problems

Phe accumulates and a secondary metabolic pathway for Phe is used

PKU if you have elevated levels of 4 compounds in urine

31
Q

THB

A

is also required for the synthesis of neurotransmitters NE & 5HT

If the cause of PKU is THB-related restricting Phe intake solves part of the problem but it is also necessary to supply precursors of the neurotransmitters

32
Q

Phenylketonuria (PKU): Consequences, Diagnosis, Treatment

A

accumulation of Phe and its metabolites may prevent (by competition) the transport of important AA’s from the blood to the brain

screening for PKU in newborn babies is easy and very cost-effective

first-line treatment is simple to restrict Phe intake and increase Tyr intake, in the diet

increase tyr because you cannot make tyr if you have PKU

anyone with PKU must avoid Aspartame a dipeptide of Asp and the Me-ester of Phe

P1 Spring 2024 (57 decks)

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