(생화학2) Fatty acid catabolism

* Chylomicron

Large fat droplet → Bile acids (from gallbladder) → Lipase (from pancreas) → Fatty acids, Monoglycerides → Triglycerides → + Phospholipids, Cholesterol, Protein → Chylomicron → Lymph (lacteal) system

• most bile acids eventually returns to gallbladder
• Apolipoproteins: B-48, C-2, C-3, …

 

* Fats → degraded into fatty acids & glycerol

• cytoplasm of adipocytes
• Glycerol → glycolysis
• Fatty acids → other tissues for fuel (beta-oxidation) (mitochondria)

 

* Regulation of Fatty acid Synthesis and Breakdown (simultaneous activation = futile cycle)

High-carbohydrate meal ⇒ blood glucose level ↑ ⇒ insulin release → (insulin-dependent protein phosphatase) ACC activate → (ACC) Actyl-CoA >> Malonyl-CoA ⇒ fatty acid synthesis & 지방산 베타 산화 억제

 

 # 지방산 베타 산화 억제

: Malonyl-CoA ⇒ inhibit Carnitine acyltransferase 1 ⇒ prevent fatty acid entry into the mitochondrial matrix(베타산화: Fatty acyl-CoA → Acetyl-CoA)

: Malonyl-CoA prevent futile cycle by preventing fatty acid transport through a membrane

+) Low blood glucose level ⇒ glucagon release → (PKA) ACC inactive

• phosphatase: dephosphorylate(인산 떼기) ↔ kinase: phosphorylate(+P)
• ACC = acetyl-CoA carboxylase
• Major regulatory control point for beta-oxidation: Carnitine acyl-transferase 1

* Glycerol → glycolysis [해당과정]

glycerol → (glycerol kinase) (ATP 사용) L-Glycerol 3-phosphate → (glycerol 3-phosphate dehydrogenase) (NADH 생성) Dihydroxyacetone phosphate → (triose phosphate isomerase) D-Glyceraldehyde 3-phosphate → Glycolysis

• NAD+ → NADH + H+
• subsequent reactions recover more than enough ATP to cover this cost
• produced rapidly from glycerol in only 3 steps
• allow an interaction between carbohydrate and lipid metabolism

* Fatty acid → transport into Mitochondria

• small FAs: diffuse freely across mitochondrial membranes
• larger FAS: transport via acyl-carnitine/carnitine transporter

1. Fatty acid → (activated to) acyl-CoAs

2. (Carnitine acyltransferase 1)acyl group is transferred to carnitine (Acyl-carnitine)

: at the outer / inter membrane

: transiently attached to the hydroxyl group of carnitine (일시적)

: acyl-carnitine = fatty acyl-carnitine

3. acyl-carnitines readily cross the mitochondrial inner membrane

: Facilitated diffusion

: Acyl-Carnitine/Carnitine transporter in the innermembrane

4. (Carnitine acyltransferase 2)acyl group is transferred to mitochondrial coenzyme A

: mitochondrial matrix

: freeing carnitine return to the intermembrane through the same transporter

: ⇒ acyl-CoA

 

* beta-oxidation

• remove one acetyl moiety (in the form of acetyl-CoA)
• from the carboxyl end
• 4 STEPs

acyl-CoA → (acyl-CoA dehydrogenase) (FADH2 생성) trans double bond → (enoyl-CoA hydratase) (+H2O) L-beta-Hydroxyacyl-CoA → (beta-hydroxyacyl-CoA dehydrogenase) (NADH 생성) beta-Ketoacyl-CoA → (acyl-CoA acetyltransferase = thiolase) (+CoA-SH) Acyl-CoA + Acetyl-CoA

• FAD → FADH2
• NAD+ → NADH + H+
• Net reaction: thiolysis of carbon-carbon bond

ex. 

Palmitate(C16) → Palmitoyl-CoA →→→→Myristoyl-CoA(C14) + Acetyl-CoA(C2)

Palmitate(C16) → + C2 → + C2 → + C2 → + C2 → + C2 → + C2 → + C2 → C2

: acetyl-CoA(C2) * 8 molecules [7steps] (1 Acetyl-CoA = 10 ATP)

(1 step = 1 FADH2 + 1 NADH = 4 ATP)

: FADH2 * 7 = 10.5 ATP

: NADH * 7 = 17.5 ATP

• Oxidation of one molecule of Palmitoyl-CoA → CO2 + H2O

: yield 108 ATP (= 10.5+ 17.5 + 10*8)

 

ex.

Stearic acid(C18)

: acetyl-CoA(C2) * 9 [8steps] (90 ATP)

FADH2 (1.5 ATP) * 8 + NADH (2.5 ATP) * 8 = 4 ATP * 8 = 32 ATP

• potential ATP yield from complete oxidation of Stearic acid(C18)

: 122 ATP

 

• Unsaturated fatty acid - Cis double bonds - required Isomerase, Reductase

: not a substrate for enoyl-CoA hydratase

• Monounsaturated fatty acids - enoyl-CoA isomerase

: reposition the double bond - starting at carbon 3 (after 3 cycles)

: converting the cis isomer to a trans isomer → 5 cycles (⇒6 acetyl-CoA)

 

ex. Oleic acid(∆9) (= oleoyl-CoA)

• Polyunsaturated fatty acids - both isomerase and reductase

acyl-CoA → 3 cycles(⇒3 acetyl-CoA) 

   → cis, cis → (enoly-CoA isomerase) trans, cis → 1 cycles(⇒1 acetyl-CoA)

   → (2,4-dienoyl-CoA reductase) (NADPH dependent) trans-∆3

   → (enoyl-CoA isomerase) trans-∆2 → 4 cycles(⇒5 acetyl-CoA)

: Additional reactant required for oxidation of polyunsaturated fatty acids compared to saturated fatty acids = NADPH

 

ex. Linoleic acid(∆9,12) (= linoleoyl-CoA)

• first double bond: requires isomerization
• second: requires reduction
• Combination action of two enzymes

: 2,4-dienoyl-CoA reductase and enoyl-CoA isomeraze

: trans-2,cis-4-dienoyl-CoA → trans-2-enoyl-CoA ⇒ beta-oxidation

1) Isomerase - 3번째 탄소에서 시작하는 cis ⇒ trans

2) Reductase - 3번째에 있지 않은 cis 이중결합 환원 (이중결합 위치 옮기기)

 

• Odd-numbered fatty acids

: Carboxylation(+HCO3-) → Isomerization to Succinyl-CoA ⇒ CAC

: Carboxylation → Conversion(Epimerization of D- to L- & Mutase:substituents exchange positions) ⇒ succinyl-CoA ⇒ CAC

 

ex. Propionyl-CoA(C3)

Propionyl-CoA 

→ (propionyl-CoA carboxylase) (+ HCO3-, ATP, Biotin) D-methylmalonyl-CoA

→ (methylmalonyl-CoA epimerase) L-methylmalonyl-CoA

→ (methylmalonyl-CoA mutase) (+ coenzyme B12) Succinyl-CoA

: most dietary fatty acids - even-numbered

↔  odd-numbered

: many plants and some marine organisms

: bacterial metabolism in the rumen of ruminants

 

* Acetyl-CoA → citric acid cycle → oxidize into CO2

: 1 Acetyl-CoA makes 10 ATP (GTP, 3NADH, FADH2)

• FADH2 = 1.5 ATP
• NADH = 2.5 ATP
• GTP = 1 ATP

* FADH2, NADH → enter ETF

• ETF

= electron transferring flavoprotein

= electron carrier of the mitochondrial respiratory chain

 

* Ketone bodies (depleted oxaloacetate)

2 acetyl-CoA → (thiolase) Acetoacetyl-CoA → (HMG-CoA synthase) (+Acetyl-CoA, H2O) HMG-CoA → (HMG-CoA lyase) Acetoacetate → Acetone or beta-hydroxybutyrate

• Ketone body formation in the matrix of liver mitochondria
• Acetoacetate → (acetoacetate decarboxylase) Acetone + CO2

OR (D-beta-hydroxybutyrate dehydrogenase) (+NADH) D-beta-hydroxybutyrate

• first step: reverse of the last step in the beta-oxidation (thiolase reaction)
• Ketone body formation release coenzyme A (⇒beta-oxidation)
• acetyl-CoA → CAC: require oxaloacetate
• depleted oxaloacetate

: gluconeogenesis (oxaloacetate → glucose: fuel for brain, other tissues)

: acetyl-CoA → Ketone bodies

• promote gluconeogenesis ⇐ diabetes, reduced food intake

→ draw off oxaloacetate

→ slow CAC, enhance the conversion(acetyl-CoA → acetoacetate: ketone bodies)