Amino metabolism - AA II

Question 1

What are the 6 final products of degredation of ALL amino acids?

Differentiate btw gluco- and ketogenic products.

Answer 1

glucogenic:

• pyruvate
• OXA
• fumarate
• succinyl CoA
• α-KG

ketogenic:

• acetyl CoA

Question 2

What is folate?

A deficiency can lead to.. ?
Why is it especially important during pregnancy?

Structure.

Answer 2

vit B₉ (folic acid)

symptoms similar to vit B₁₂ deficiency: megaloblastic edema, CNS problems

⇒ early administration during pregnancy decr. risk for spina bifida

Question 3

Which enzyme forms tetrahydrofolate from folate?

Reaction.

Answer 3

dihydrofolate reductase = DHFR
in 2 steps, each step requires 1 NADPH/H⁺

folate → dihydrofolate (H₂F) → tetrahydrofolate (H₄F)

⇒ active form of folate, can enter folate cycle

Question 4

What is the function of tetrahydrofolate?

List the main steps of the folate cycle and its products.

Answer 4

tetrahydrofolate = methyl-group donor
stepwise receiving more hydrogen during folate cycle

1. H₄F + Trp/His → methenyl-H₄F (CH-H₄F)
2. … + Ser/Gly → methylene-H₄F (CH₂-H₄F)
3. … →​ methyl-H₄F (CH₃-H₄F)
4. … → transfer of CH₃- to HomoCys, restoring H₄F

Question 5

Which first intermediates are formed in step 1 of the folate cycle?

How are these products used?

Answer 5

H₄F either reacts w/

• His → formimino-H₄F, or
• Trp → formyl-H₄F

⇒ can further be used for nucleotide synthesis, or continue in folate cycle

Question 6

What happens to formimino-H4F and formyl-H4F to continue in the folate cycle?

Answer 6

• formimino-H₄F gives off NH₄⁺
• formyl-H₄F gives off H₂O

→ to form methenyl H₄F (CH-H₄F)

Question 7

What happens with CH-H₄F in the folate cycle?

How can its product be used further?

Answer 7

CH-H₄F + NADPH + Ser/Gly
→ CH₂-H₄F + NADP⁺

(methenyl becomes methylene)

⇒ either used for dTMP synthesis, or continues further in folate cycle

Question 8

Which enzyme catalyzes the conversion of CH₂-H₄F in the folate cycle?

Reaction.

Answer 8

methylene H₄F reductase = MTHFR

• *CH₂-H₄F** + NADH →
• *CH₃-H₄F** + NAD⁺

(methylene to methyl)

_{MoTHereFuckeR}

Question 9

Draw the structures for

• Cys
• HomoCys
• Met
• Ser
• HomoSer

Answer 9

Question 10

What is the function of the SAM cycle?

List the main products of all steps.

Answer 10

degradation of Met + activation of -CH₃ groups

1. ​​Met → SAM
2. … → SAH
3. … → HomoCys
4. last step = also last step of folate cycle, restores H₄F and Met_​_

Question 11

Which enzyme catalyzes the conversion of Met in the SAM cycle?

Reaction.

Answer 11

Met adenosyl transferase
adenosyl-terminal of ATP transferred to -S of Met,
activation of -CH₃ by formation of SAM

Met + ATP → PP_i + P_i + S-adenosyl-Met (SAM)

Question 12

Which group of enzymes use SAM as a substrate?

Reaction.

Answer 12

SAM dependent methylases
decarboxylation (energy rich -CH₃) of SAM to form SAH

SAM + … → -CH₃ + S-adenosyl-HomoCys (SAH)

Question 13

Which enzyme catalyzes the conversion of SAH in the SAM cycle?

Reaction.

Answer 13

SAH hydrolase
hydrolysis

SAH + H₂O → adenosine + HomoCys

Question 14

Which enzyme catalyzes both, the last step of SAM and folate cycle?

Reaction.

Answer 14

HomoCys methyltransferase
remethylation of Met to start SAM cycle again

HomoCys + CH₃-H₄F + → Met + H₄F

⇒ all original substrates reformed

Question 15

What is another name for HomoCys methyltransferase?

What is its prosthetic group?

Answer 15

= Met synthase

→ prosthetic group: methylcobalamin (vit B₁₂)

_{<u>NOTE:</u> also prosth. group of methylmalonyl-CoA mutase}

Question 16

Describe the molecular effects of folate or vit B₁₂ deficiency.

Answer 16

• ↑HomoCys, ↑adenosine in blood
• methyl-trap (↑methyl-H₄F, ↓methylene-H₄F)
• ↓ dUMP → decr. dTMP/purines levels/cell division

_{vit B12 def. also causes <u>methylmalonic aciduria</u> <em>(cf. own card)</em>}

Question 17

What are the 2 pathways that HomoCys can enter?

Answer 17

• SAM cycle (last step) → regeneration of Met and H₄F
• synthesis of Cys + α-ketobutyrate
  → eventually formation of succinyl-CoA

Question 18

As a summary…

Which AAs are degraded to succinyl CoA?

Answer 18

• Ile
• Val
• Met
• Thr

Question 19

Which enzymes are responsible for the formation of Cys from HomoCys?

Reactions.

How do you call the entire mechanism?

Answer 19

1. cystathionine synthase
   HomoCys + Ser → cystathionine + H₂O
2. cystathionine lyase
   cystathionine + H₂O → Cys + α-ketobutyrate + NH₄⁺

​= transsulfuration

Question 20

What is the prosthetic group fo cystathionine synthase?

Answer 20

PLP (vit B₆)

Question 21

What are the consequences of a cystathionine synthase deficiency?

Answer 21

no formation of cystathionine from HomoCys
→ ↑ HomoCys → hyperhomocystinemia

⇒ atherosclerosis, incr. risk of Alzheimer’s

Question 22

Which AAs are converted to α-ketobutyrate?

Answer 22

• Met via HomoCys/cystathionine
• Thr by Ser-Thr dehydratase

Question 23

What are the 2 mechanisms of Thr degradation?

Glucogenic or ketogenic?

Answer 23

• Ser-Thr dehydratase (very low amount)
  … → α-ketobutyrate → succinyl CoA (glucogenic)
• Thr aldolase
  Thr → acetaldehyde + Gly (glucogenic/ketogenic)
  … → acetyl-CoA

Question 24

List the 3 steps that are necessary for degradation of α-ketobutyrate.

Answer 24

1. α-ketobutyrate → proprionyl CoA
2. … → D-methylmalonyl CoA
3. via intermediate rearranged to succinyl CoA

Question 25

Which enzyme catalyzes the first step of formation of succinyl CoA from α-ketobutyrate?

Answer 25

a-ketobutyrate dehydrogenase complex

α-ketobutyrate + NAD⁺ → CO₂ + prioprionyl CoA + NADH

Question 26

During the catabolism of which AA (and other substances) is proprionyl CoA formed?

Answer 26

• all AA that are degraded to succinyl CoA
  → Met, Thr, Val, Ile
• furthermore:
  
  • by-product of conversion of chol to bile acids
  • degradation of odd-chain FAs
  • degradation of thymine

Question 27

Which enzymes catalyzes the reaction of proprionyl-CoA to eventually form succinyl-CoA?

Reaction.

Answer 27

proprionyl CoA carboxylase

proprionyl CoA + ATP + CO₂ →
D-methylmalonyl CoA + ADP + P_i

Question 28

What is the cofactor of proprionyl CoA carboxylase?

Answer 28

biotin

Question 29

Which 2 enzyme catalyzes the conversion of methylmalonyl CoA to eventually form succinyl-CoA?

Reaction.

Answer 29

1. methylmalonyl CoA racemase D → L
   isomerization of D- to L-methylmalonyl CoA
2. methylmalonyl Coa mutase
   rearrangement to succinyl CoA

Question 30

As a summary…

Which AA are broken down to succinyl CoA?

What do they all have in common?

Answer 30

​succinyl-CoA = intermediate of citrate cycle
→ glucogenic

• Met
• Thr
• Ile
• Val

⇒ essential AA

Question 31

What is the prosthetic group of methylmalonyl CoA mutase?

It is also the prosthetic group of which 2nd enzyme?

Answer 31

vit B₁₂ = cobalamin

• 5’adenosyl cobalamine → methylmalonyl CoA mutase
• methylcobalamine → HomoCys methyltransferase

Question 32

What are causes of methylmalonic aciduria?

Answer 32

↑ methylmalonate in plasma
→ excretion via urine

• vit B₁₂ deficiency
• deficiency of methylmalonyl mutase

_{<strong>​</strong><u>NOTE:</u> [methylmalonate] = marker for vit B12 supply}

Question 33

Which AA constitute to the group of BCAAs?

Essential/semi-essential/non-essential?

What is their function?

Answer 33

Val, Leu, Ile → branched chain AAs

• essential AAs
• important for muscle metabolism, indicate nutritional status of organism
• have a similar pathway of catabolism

Question 34

Describe the common degradational pathway of BCAAs.

Which enzymes are responsible for it?

Answer 34

degraded in 3 steps, first 2 steps are same for all three

1. BCAA transaminase
   transamination of each AA to its α-ketoacid
2. BC α-ketoacid dehydrogenase (BCKD)
   dehydration/decarboxylation to acyl CoA derivative
3. reactions similar to β-oxidation, hence prod of NADH, FADH₂

Question 35

What is special about the branched chain α-ketoacid dehydrogenase?

Answer 35

catalyzes 2nd step of degradation of BCAAs

similar to pyruvate dehydrogenase complex
= reaction mechanism/coenzymes needed

→ NAD, TPP, lipoic acid, FAD, CoA-SH

Question 36

As a summary…

Which AAs are degraded to acetyl CoA (directly)?

Answer 36

Ile​

Question 37

Describe the degradation of Val.

List enzymes/intermediates.

Answer 37

1. BCAA transaminase: Val → α​-keto-isovalerate
2. BCKD: … → isobutiryl CoA
3. ind. degr.: … → proprionyl CoA

Question 38

Describe the degradation of Ile.

List enzymes/intermediates.

Answer 38

1. BCAA transaminase: Ile → α-keto-β-methyl-glutarate
2. BCKD: … → α-methyl-butiryl-CoA
3. ind. degr.: … → acetyl CoA + proprionyl CoA

Question 39

Describe the degradation of Leu.

List enzymes/intermediates.

Answer 39

1. BCAA transaminase: Leu → α-keto-isocapronate
2. BCKD: … → isovaleryl CoA
3. ind. degr.: … → HMG CoA → acetyl CoA + acetoacetate

Question 40

What is the metabolic relevance of Leu?

Answer 40

• precursor of FAs and ketone bodies
• enhances secretion of insulin

Question 41

What is the consequence of a deficiency of BCKD?

Answer 41

maple syrup urine disease
↑excretion of BCAAs + their α-ketoacids via urine

⇒ ketoacidosis, mental retardation, death if not diagnosed early enough

Question 42

Which AAs form OXA as their final product of degradation?

What do they have in common?

Answer 42

OXA = intermediate in citrate cycle
→ glucogenic

• Asn → Asp

⇒ non-essential AAs

Question 43

How is Asn catabolized and synthesized?

Enzymes + catalyzed reactions.

Answer 43

• catabolized by asparaginase: (cf. own card)
  Asn + H₂O → Asp + NH₄⁺
• synthesized by Asn synthetase: (cf. own card)
  Gln + Asp + ATP → AMP + PP_i + Glu + Asn

Question 44

Which enzyme regulates the concentration of Asp?

Reaction.

Answer 44

ASAT = reversible transamination

α-KG + Asp ⇔ Glu + OXA

Question 45

Which AAs act as amino group donors?

Answer 45

• Gln, Glu
• Asp

Question 46

In which reactions does Asp act as amino group donor?

Name enzyme + reaction.

Answer 46

→ fumarate remains (instead of OXA)

• in urea cycle: arginosuccinate lyase
  arginosuccinate → Arg + fumarate
• AMP synthesis: adenylosuccinate lyase
  adenylosuccinate → AMP + fumarate