Amino metabolism - AA II Flashcards by LV D

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

Differentiate btw gluco- and ketogenic products.

glucogenic:

pyruvate
OXA
fumarate
succinyl CoA
α-KG

ketogenic:

acetyl CoA

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What is folate?

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

Structure.

vit B₉ (folic acid)

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

⇒ early administration during pregnancy decr. risk for spina bifida

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Which enzyme forms tetrahydrofolate from folate?

Reaction.

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

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What is the function of tetrahydrofolate?

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

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

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

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

How are these products used?

H₄F either reacts w/

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

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

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

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

→ to form methenyl H₄F (CH-H₄F)

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What happens with CH-H₄F in the folate cycle?

How can its product be used further?

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

(methenyl becomes methylene)

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

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

Reaction.

methylene H₄F reductase = MTHFR

*CH₂-H₄F** + NADH →
*CH₃-H₄F** + NAD⁺

(methylene to methyl)

_{MoTHereFuckeR}

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Draw the structures for

Cys
HomoCys
Met
Ser
HomoSer

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What is the function of the SAM cycle?

List the main products of all steps.

degradation of Met + activation of -CH₃ groups

Met → SAM
… → SAH
… → HomoCys
last step = also last step of folate cycle, restores H₄F and Met__

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

Reaction.

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)

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Which group of enzymes use SAM as a substrate?

Reaction.

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

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

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

Reaction.

SAH hydrolase
hydrolysis

SAH + H₂O → adenosine + HomoCys

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

Reaction.

HomoCys methyltransferase
remethylation of Met to start SAM cycle again

HomoCys + CH₃-H₄F + → Met + H₄F

⇒ all original substrates reformed

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What is another name for HomoCys methyltransferase?

What is its prosthetic group?

= Met synthase

→ prosthetic group: methylcobalamin (vit B₁₂)

_{NOTE: also prosth. group of methylmalonyl-CoA mutase}

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Describe the molecular effects of folate or vit B₁₂ deficiency.

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

_{vit B12 def. also causes methylmalonic aciduria (cf. own card)}

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What are the 2 pathways that HomoCys can enter?

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

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As a summary…

Which AAs are degraded to succinyl CoA?

Ile
Val
Met
Thr

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

Reactions.

How do you call the entire mechanism?

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

= transsulfuration

What is the prosthetic group fo cystathionine synthase?

PLP (vit B₆)

What are the consequences of a cystathionine synthase deficiency?

no formation of cystathionine from HomoCys
→ ↑ HomoCys → hyperhomocystinemia

⇒ atherosclerosis, incr. risk of Alzheimer’s

Which AAs are converted to α-ketobutyrate?

Met via HomoCys/cystathionine
Thr by Ser-Thr dehydratase

What are the 2 mechanisms of Thr degradation?

Glucogenic or ketogenic?

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

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

α-ketobutyrate → proprionyl CoA
… → D-methylmalonyl CoA
via intermediate rearranged to succinyl CoA

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

**_a-ketobutyrate dehydrogenase complex_** α-ketobutyrate + NAD⁺ → CO₂ + prioprionyl CoA + NADH

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

* 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**

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

**_proprionyl CoA carboxylase_** proprionyl CoA + ATP + CO₂ → D-methylmalonyl CoA + ADP + P_i

What is the cofactor of proprionyl CoA carboxylase?

**biotin**

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

1. **_methylmalonyl CoA racemase D → L_** isomerization of _D- to L_-methylmalonyl CoA 2. **_methylmalonyl Coa mutase_** rearrangement to succinyl CoA

As a summary... Which AA are broken down to succinyl CoA? What do they all have in common?

succinyl-CoA = intermediate of citrate cycle → glucogenic * **Met** * **Thr** * **Ile** * **Val** ⇒ essential AA

What is the prosthetic group of methylmalonyl CoA mutase? It is also the prosthetic group of which 2nd enzyme?

**vit B₁₂ = cobalamin** * 5'adenosyl cobalamine → _methylmalonyl CoA mutase_ * methylcobalamine → _HomoCys methyltransferase_

What are causes of methylmalonic aciduria?

↑ methylmalonate in plasma → excretion via urine * **vit B₁₂ deficiency** * **deficiency of methylmalonyl mutase** _{NOTE: [methylmalonate] = marker for vit B12 supply}

Which AA constitute to the group of BCAAs? Essential/semi-essential/non-essential? What is their function?

_**Val, Leu, Ile** → branched chain AAs_ * _essential AAs_ * important for muscle metabolism, indicate nutritional status of organism * have a similar pathway of catabolism

Describe the common degradational pathway of BCAAs. Which enzymes are responsible for it?

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

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

_catalyzes 2nd step of degradation of BCAAs_ **similar to pyruvate dehydrogenase complex** = reaction mechanism/coenzymes needed → NAD, TPP, lipoic acid, FAD, CoA-SH

As a summary... Which AAs are degraded to acetyl CoA (_directly_)?

**Ile**

Describe the degradation of Val. List enzymes/intermediates.

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

Describe the degradation of Ile. List enzymes/intermediates.

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

Describe the degradation of Leu. List enzymes/intermediates.

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

What is the metabolic relevance of Leu?

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

What is the consequence of a deficiency of BCKD?

**_maple syrup urine disease_** ↑excretion of BCAAs + their α-ketoacids via urine ⇒ ketoacidosis, mental retardation, death if not diagnosed early enough

Which AAs form OXA as their final product of degradation? What do they have in common?

OXA = intermediate in citrate cycle → glucogenic * **Asn → Asp** ⇒ _non-essential AAs_

How is Asn catabolized and synthesized? Enzymes + catalyzed reactions.

* _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

Which enzyme regulates the concentration of Asp? Reaction.

**ASAT** = reversible transamination ## Footnote **α-KG + Asp ⇔ Glu + OXA**

Which AAs act as amino group donors?

* **Gln, Glu** * **Asp**

In which reactions does Asp act as amino group donor? Name enzyme + reaction.

→ **fumarate remains** (instead of OXA) * _*in urea cycle:* **arginosuccinate lyase**_ arginosuccinate → Arg + fumarate * _*AMP synthesis:* **adenylosuccinate lyase**_ adenylosuccinate → AMP + fumarate

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Amino metabolism - AA II Flashcards

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