1-7 Lipid Metabolism Flashcards
Fatty Acid Oxidation overview
Mjor source of E btw meals and during increased demand
during fasting provides ketone bodies as fuel
higher E yield per mole than glucose
mito matrix
Transport of FA in mito
Cytosol
1. Long chain FA + ATP + coA via ACYL COA SYNTHESTASE -> Fatty acyl CoA + AMP +PPi
Intermembrane space
- Fatty acyl CoA move to interembrane space
- Fatty actyl CoA + Carnitine via CPT1 ->CoA + Fatty acylcarnitine
Matrix
- Fatty acylcarnitine via CARNITINE ACYLCARNITINE TRANSLOCASE move to matrix
- Fatty acylcarnitine + CoA via CPT2 -> Fatty acyl coA (ready for b oxida) + Carnitine (shuttled back into intermembrane space)
Short and medium chain FAs can be shuttle direction through MCT into matrix
B oxidation
- oxidation: ACYL COA DEHYDROGENASE- oxidizes FA to a double bond and reduces FAD to FAD(2H) (1.5 ATP)
- hydration: ENOYL COA HYDRALASE- adds H2O
- oxidation: B-HYDROXY ACYL DEHYDROGENASE- oxidizes FA alcohol to ketone reduces NAD+ to NADH + H+ (2.5ATP)
- cleavage: B-KETO THIOLASE- cleaves 2 carbons and adds coA to make acetyl coA + shortened FA-coA
Oxidation of Odd chain FA
Odd chain FA b-oxi to propionyl-CoA
- propionyl-CoA + ATP +CO2-biotin via PRIOPIRONYL-COA CARBOXYLASE -> AMP + PPi + methyl malonyl-coA // intermediate // succinyl coA (citric acid cycle)
Essentially: can move 3C FA to citric acid cycle via rearrangement and energy
ATP yield from b-oxi of palmitate
7 oxidation spirals:
7 FAD(2H) = 10.5 ATP from oxi phos 7 NAD(2H) = 17.5 ATP from oxi phos 8 AcetylCoA = 80 ATP from oxidation in TCA
Required 2 ATP from activation step to get across cytosol membrane
Sum: 106 ATP
Regulation of B oxidation
+: High levels of FA induce transcription of enzyme genes
Fatty acyl CoA –> Fatty acyl carnitine, inhibited by malonyl coA (it is intermediate of FA synth!)
ATP/ADP ratio high inhibits ETC thereby increases NADH and FAD(2H) which inhibits B-oxidation (because they are products)
Essentially: reduce Boxi when ATP high
Peroxisomes
**oxidation of very long chain FAs, contain catalase
detox of phenols fraldehyde alchohols
Synth plasmalogens
**Long chain FA-coA + FAD via OXIDASE -> FAD(2H) + shorterFA-coA (can now be transformed to acetyl carnitine or SCFA-carnitine and shuttles to mito matrix)
FAD(2H) + O2 -> H2O2 (Toxic) via CATALASE -> H2O + .5 O2
alpha oxidation of phytanic acid in peroxisomes
branched FA, alphaoxidation cleaves branches so betaoxidation can occur
omega oxidation
in ER, omega carbon is farthest away from carbonyl
- methane oxidized to alcohol further oxidized to carboxylic acid, compound now a dicarboxylic acid (very soluble)
Oxidation of ketone bodies
in peripheral tissues
- Beta-hydroxybutyrate (alcohol) + NAD+ via B-HYDROXYBUTYRATE DEHYDROGENASE -> NADH + H+ + acetoacetate (ketone)
- acetoacetate + Succinyl coA(from TCA) via TRANSFERASE -> acetoacetyl coA + succinate
- acetyoacetyl coA + coASH via THIOLASE -> 2 acetylCoA
Alcohol metabolism
- Ethanol + NAD+ via ALCOHOL DEHYDRGENASE CYTOSOL -> NADH + H+ + Acetaldehyde
- Acetaldehyde + NAD+ via ACETALDEHYDE DEHYDROGENASE MITOCHONDRIA -> Acetate + ANDH + H+
- Acetate + coASH + ATP via ACETYL COA SYNTHETASE -> acetylcoA
Also happens on membrane of ER with MEOS (microsomal ethanol oxidizing system) to turn ethanol to acetaldehyde
FA synth: production of cytosolic acetylcoA
Cytosol
1. Glucose via glycolysis -> pyruvate
Mitochondria
- pyruvate via PYRUVATE CARBOXYLASE -> OAA
- 1 pyruvate PYRUVATE DEHYDROGENASE -> Acetyl coA
- OAA + Acetylcoa -> citrate, exits mitochondria
Cytosol
- citrate via CITRATE LYASE -> OAA + AcetylcoA (for FA synth)
- 1 OAA + NADH via CYTOSOLIC MALATE DEHYDROGENASE -> Malate + NAD+
- Malate + NADP+ via MALIC ENZYME -> Pyruvate (ready to cycle into mitochondria) + CO2 + NADPH
FA synth: sources of NADPH
- Pentose Phosphate pathway: G6P + NADP+ -> F6P + NADPH
2. Malate + NADP+ -> Pyruvate + NADPH
FA synth: Synthesis of malonylCoA
Citrate in cytosol -> OAA + Acetyl coA
- Acetyl coA + CO2(biotin) + ATP via ACETYL COA CARBOXYLASE -> ADP + Pi + Malonyl coA
reversed with MALONYL COA DECARBOXYLASE
Regulation of acetyl coA carboxylase
Cytosol:
Acetyl coA + CO2(biotin) + ATP via ACETYL COA CARBOXYLASE -> ADP + Pi + Malonyl coA
Direct:
+: Citrate
-: Palmitoyl coA
Phosphorylation inactivates
AMP-activated protein kinase adds P group (increased activity under low energy levels)
Phosphatase removes P group (increased activity under high insulin levels)
Regulation of CPT1
Cytosol:
Malonyl CoA inhibits CPT1 to stop transport of FAcoA+Carnitine into intermembrane space, because malonyl coA substrate for FA synthase and wants to inhibit b oxidation of FAs
Synthesis of palmitate
on FATTY ACID SYNTHASE on cytosolic side of ER
AcetylcoA gives the first C, all others from malonylcoA
- Condensation: removes CO2 and coASH
- Reduction: NADPH to NADP+
- Dehydration: removes H2O
- Reduction: NADPH to NADP+
Adds 2 Cs at a time
Desaturation of FAs
saturated FA + O2 +2H+ via FATTY ACYL COA DESATURASE -> H2O + Monosaturate FAcylCoA
This can happen at C9, C5, C6
Synth Ketone bodies (when, where, mech)
When: fasting, carb restriction
Where: mitochondria of hepatocytes
- 2 acetylCoA via THIOLASE -> coASH + acetoacetylCoA
- acetoacetylCoA + acetylcoA via HMG COA SYNTHASE -> HMGcoA
- HMGcoA via HMG COA LYASE -> acetylcoa + acetoacetate
- acetoacetate +NADH+H via B HYDROXYBUTYRATE DEHYDROGENASE-> B-hydoxybutyrate + NAD+
- 1 acetoacetate spontaneous loss of CO2 -> acetone
Regulation of ketone body synthesis
- ) High levels of FA lead to
- ) high levels of CPT1 and thereby low levels of malonyl coA
- ) This produces high levels of FA-carnitine transformed to FA-CoA in mido matrix, and high levels of ATP from ETC inhibit Boxidation process but
- )b oxidation occurs producing high levels of acetyl coA which are transformed to acetoacetyl coA and then produce ketone bodies
- acetyl coA could also be transformed to citrate but ISOCITRATE DEHYDROGENASE in inhibited by high NADH so cannot catalyze rxn to malate - ) OAA is being converted to malate because high NADH levels (OAA + NADH -> NAD+ + malate), malate sent for gluconeogenesis
Ketogenic AAs
Source of keton bodies during starvation, produce acetyl coA and or acetoacetate
Synth of triacylglycerol
Liver: glycerol + ATP via GLYCEROL KINASE -> ADP + Glycerol3p
Liver/adipose: Glucose -> Dihydorzyacetonephosphate->Glycerol3P
Glycerol3P -> Phosphatidic acid -> DAG -> triacylglycerol (blood vldl OR adipose stores)
Degradation of triacylglycerol (type of enzyme)
Done with lipases
Synth membrane phospholipids (2 routes, starting material)
Phosphatidic acid
Route 1:
- Phosphatidic acid -> DAG + Pi
- DAG + CDP-headgroup -> Glycerophospholipid + CMP
- Glycerophospholipid forms “phosphatidyl”choline, ““ethanolamine, ““serine
Route 2:
- Phosphatidic acid +CTP -> CDP-DAG + PPi
- CDP-DAG + headgroup -> Glycerophospholipid + CMP
- Glycerophospholipid forms “phosphatidyl”inositol, cardiolipin, ““glycerol
Isoprenoid / Cholesterol synthesis
- Acetyl-coA + acetoacetyl-coA -> HMG-CoA
- HMG-CoA +2NADPH via HG COA REDUCTASE (inhibited by statins) -> mevalonate + NADP+
- mevalonate -> isopentenylPP // dimethylallylPP -> geranyl ->farnesyl->squalene —-> cholesterol
