Flashcards in Fatty Acid Metabolism Deck (35):
FA synthesis location
Also, in adipose tissue, brain, kidneys, lactating mammary glands
How citrate gets from mitochondria to cytosol?
citrate —> Acetyl-CoA
Inhibited by: PUFA, leptin
Stimulated by: Glucose, Insulin
Acetyl-CoA Carboxylase (ACC)
Acetyl-CoA —> Malonyl-CoA
-Requires ATP, CO2 and Biotin as a CO-FACTOR
-RATE-LIMITING ENZYME in FA synthesis
Stimulated by - Citrate (+)
Inhibited by - Long chain fatty acids I.e. palmitate (-)
ACC dimeric form = inactive, polymeric form = active
What does Malonyl-CoA inhibit?
-Enzyme in FA degradation
-Rate limiting step in the degradation
Prevents FA synthesis and degradation from occurring simultaneously
Substrate for Fatty Acid Synthase Complex (last phase of FA synthesis)
Requires 7 Malonyl-CoA molecules.
Malonyl-CoA is a 3C molecule, FA Synthase adds on 2 carbons from Malonyl-CoA to a growing fatty acid each time.
1 Acetyl-CoA (2C) + 7 Malonyl-CoA (2C each = 14C) —> 16C Palmitate
Fatty Acid Synthase
Multi-enzyme complex with 2 identical diners (260 kDa each)
- arranged in head to tail conformation
Each dimmer contains 7 enzyme activities plus an Acyl Carrier Protein (ACP)
Order of reactions catalyzed by Fatty Acid Synthase (FAS)
(Then repeat steps 2-4 x6)
What is the source of NADPH in FA synthesis?
Malic enzyme: 1
Hormone secreted by adipose tissue. “Fat-Brain axis”
Communicates with the brain (hypothalamus) to reduce food intake when the body is fed/full. Regulates body weight
Leptin K/O mice = obese
-If mice are given leptin —> weight reduced
Where is palmitate converted to longer-chain FA?
Smooth Endoplasmic Reticulum or Mitochondria
-Brain requires longer chain FA (C18-24)
SER uses Malonyl-CoA as carbon donor
Mitochondria uses Acetyl-CoA as carbon donor
Acyl CoA Desaturase
Introduces double bonds in FA’s.
-Occurs in the SER and uses NADPH
Cannot synthesize double-bond beyond C9-10 in humans (i.e. omega-3), must be obtained from diet.
Insulin increases expression
PUFA suppress expression
Dietary cholesterol induces expression of delta9-Desaturase and suppresses all others
Fatty acid lengths regarding mitochondrial entry
Can diffuse into mitochondria:
-Short chain FA (SCFA)
-Medium chain FA (MCFA)
Need to be actively transported in:
-Long chain FA (LCFA)
-Very long chain FA (VLCFA) —>oxidized in peroxisomes to LCFA —> Carnitine shuttle
Fatty Acyl CoA Synthetase
In cytoplasm, adds a CoA to fatty acid —> Fatty Acyl CoA, so it can pass through the Outer Mitochondrial Membrane
-thioester bond formed between FA and Acyl CoA
Carnitine Palmitoyltransferase I (CPT-I)
Located in intermembrane space
-Catalyzes FA-CoA —> FA-Carnitine
RATE LIMITING ENZYME for FA degradation
Inhibited by Malonyl-CoA
Carnitine-Acylcarnitine Translocase (CACT)
Transports FA-Carnitine into mitochondrial matrix.
-Antiporter: FA-Carnitine (in) Carnitine (out)
Located on inner mitochondrial membrane
-Catalyzes FA-Carnitine —> (back to) FA-CoA
FA-CoA now in the matrix —> Ready of beta-oxidation
Order of steps of B-oxidation
Acyl CoA dehydrogenase (ACAD)
First enzyme in FA degradation
-Oxidizes FA via FAD+ —>FADH2 (to CoQ in ETC = 1.5 ATP)
Four types of ACADs:
Short Chain Acyl CoA Dehydrogenase (SCAD)
Medium chain ————————-—- (MCAD)
Long Chain ——— ————————(LCAD)
Very Long Chain —————————(VLCAD)
Enol CoA Hydratase
Step 2 in FA degradation: Hydration - adds water to the alkene forming beta-hydroxy Acyl CoA
Beta-hydroxyl Acyl CoA dehydrogenase
Step 3 of FA degradation - oxidizes the beta carbon to form double bond.
-NADH produced (2.5 ATP in ETC)
Acyl CoA acyltransferase (beta ketothiolase)
Last enzyme in FA degradation
Attaches sulfur of a new CoA to ketone formed after cleavage of Acetyl-CoA from Fatty Acyl chain —-shortened by 2 carbons
Acetyl-CoA = 12 ATP
ATP generated from beta-oxidation of palmitic acid
Propionyl CoA Carboxylase
First enzyme in degradation of Odd #C FA chain once FA is degraded down until Propionyl-CoA remains.
Carboxylates Propionyl-CoA —> Methylmalonyl-CoA
Methylmalonyl CoA Mutase
2nd enzyme used in odd #C FA degradation.
Catalyzes Methylmalonyl CoA —> Succinyl-CoA
Succinyl-CoA enters TCA cycle
Reductase and Isomerase
Enzymes used in degradation of UNsaturated FA.
Reductase: reduces double bond
Isomerase: moves disruptive bond
Degrade VLCFAs greater than 20C.
Beta-oxidizes but FADH produced but electron energy transferred to O2 to make H2O2 instead of TCA.
First step catalyzed by Acyl-CoA oxidase
When FA < 20 —> Sent to mitochondria for further beta-oxidation
Disorder of FA beta-oxidation that impairs breakdown of MCFAs.
-Leads to secondary Carnitine deficiency = excessive excretion of MCA carnitines in urine
-C8 FA accumulate in liver - poisonous and interferes with urea cycle - elevated ammonia
-Patient requires glucose as energy source
-Hypoglycemia/sudden death without timely intervention
Three ketone bodies
1. Acetoacetate - 23 ATP
2. Beta-hydroxybutyrate - 26 ATP
Ketone body properties and purpose
Water-soluble, acidic compounds
Provide energy for peripheral tissues during fasting/starvation
Where are ketone bodies produced?
Liver only - Mitochondrial matrix of hepatocytes
Where/when ketone bodies are used?
Brain: Starvation when glucose is completely depleted
Muscle: During fasting
Kidneys: During fasting
Occurs when glucagon/insulin ratio is high - Favoring FA breakdown
Increased Acetyl-CoA and hepatic mitochondria —> increased ketone bodies
Acetoacetate and b-hydroxybutyrate are strong acids —> lower blood pH causing acidosis. Increased concentration found in urine