L2 - Ketones and FA Synthesis

ketone bodies

low blood sugar / diabetes / fasting

liver synthesizes, extrahepatic tissues uses for glycolysis

FA break down > ACoA

acetoacetate

A primary ketone body that can be converted into acetone or reduced to β-hydroxybutyrate. It’s used by tissues for ATP production via conversion back to acetyl-CoA.

D-B-Hydroxybutyrate

ketogenesis in the liver

*thioLACE ties 2 ACES together, synthetase adds ACoA, lyase lets go ACoA, decarboxylase loses CO2, dehydrogenase reduces it

*TSLAB

thiolase + 2ACoA > + AACoA + CoASH

HMGCoASase + AACoA + ACoA + H2O > HMGCoA

HMGCoALase + HMGCoA > AAc (exported+ ACoA

AAcDClase + AAc > Acetone (exhaled) + CO2

DBHBDHase + AAc + NADH > DBHB (exported)

reverse ketogenesis in extrahepatic (non liver) tissues

DBHBDHase + DBHB + NAD+ > AAc

• forms acetoacetate via DHase (reverse of previous step)

BKACoATase + SCoA + AAc >AACoA + Succ

• forms acetoacetylCoA and succinate using succCoA and BKACoATrase

Thiolase + AACoA + CoASH > 2ACoA

• forms 2ACoA using CoASH and thiolase

fasting and starvation

FA in lipid droplets in hepatocytes go thru Boxidation > ACoA

• ACoA should > Krebs but cant

ACoA > KB formation which supplies CoA for Boxidation (pos feedback)

AAc, DBHB, acetone > energy for body / exhaled

FA Synthesis

make long chain FA, in liver and fat

highly regulated and expensive

FA Synthesis overall reaction

8ACoA + 14NADPH + 7ATP + 14H+ >

Palmitate C16 + 14NADP+ + 8CoA + 7ADP + 7Pi + 6H2O

formation of malonylCoA

cat by ACC (Acetyl CoA Carboxylase), needs biotin as CO2 carrier

ACC + ACoA + HCO3- + ATP > MCoA +ADP + Pi

central to regulation of FA synthesis

ACC

has biotin carboxylase, transcarboxylase, and biotin carrier protein domains

regulated by covalent modifications and allosteric control

1. HCO3 binds BClase domain

2. biotin arm swings over to BClase

3. 180 turn to TClase domain where ACoA is bound

4. CO2 from HCO3 + ACoA > MCoA leaving enzyme

FA Synthase enzyme

KS = synthase, thiol group

MAT = transferase

DH = DHatase

ER = reductase

KR = reductase, has ACP

ACP = acyl carrier protein, thiol group, activate Carbonyl groups

activation of FA synthesis part 0

KS primed with 1ACoA on thiol group, product CoASH

MCoA loaded on ACP, product CoASH, both thiol groups now occupied and nearby

Malonyl CoA

CO2-CH2-C=O-SCoA

A 3-carbon intermediate formed by ACC; provides 2-carbon units for elongation in fatty acid synthesis. Also inhibits carnitine shuttle to prevent simultaneous β-oxidation.

FA S Step 1 Condensation

MCoA CO2 attacks Carbonyl on KS > BKB-ACP (4C) + CO2

FA S Step 2 Reduction

ACP carries to DH are + NADPH, end =O > OH

FA S Step 3 Dehydration

BHB-ACP to DH> tdelta2BE-ACP

-OH > C=C

FA S Step 4 Reduction

tD2BE-ACP + NADPH > By-ACP (4C sat. chain)

done in ER

FA S Step 5 Transfer

ACP 4C > KS 4C so ACP can restart

FA S Extension

repeat process until 16C carbon

thioesterase Hlyzes final bond to restart

FA Synthesis Overal Process

*MASRD = malonyl, activation by ACoA, condensation by KS, reduction by KR, dehydration by DH,

(malonyl formation and activation) 1. Condensation 2. Reduction 3. Dehydration 4. Reduction 5. Translocation 6. Extension

1) 7ACoA + 7CO2 + 7ATP > 7MCoA + 7ADP + 7Pi

2) ACoA + 7MCoA + 14NADPH + 14H+ > Palmitate + 7CO2 + 8CoA + 14NADP+ + 6H2O

7ATP + 14NADPH + 14H+ > Palmitate + 7ADP + 7Pi + 14NADP+ + 6H2O

thioesterase

Hlyze thioester group

acetate transport

FA is in cytoS, ACoA is stored in mitoC cause Box / PDH

no ACoA transporter, only citrate

pull cit out of CAC in mitoC cause body is high energy

Long Chain FA

>16C, must be from diet

elongated by elongases

or desaturation by desaturases

primary metabolic source of reducing power required for FA synthesis and desaturation

oxidative phase of PPP, bc NADPH is red agent in FA synthesis

regulation of FA synthesis

metabolic intermediates regulate ACoAClase

Ggon, epi, AMP, PalmitoylCoA all inhibit

citrate activates MCoA inhibits carnitine acyltransferase

CAT1 carnitine acyltransferase I inhibited by

MalonylCoA

regulation of FA Boxidation and synthesis

Synthesis

• ACC Plated by PKA to inactive

• ACC DP by Ptase to active, which makes ACoA > MCoA

• glucgaon DA PKA, insulin A Ptase

Oxidation

• MCOA inhib CAT1 FACoA > FAcarnitine

control by glucagon

binding of glucagon to plasma receptor in subsequent P of enzymes by kinases

• ACoAClase inhibited, dec FA Synthesis

• HSL activated, inc stored fat mobilization

• PDHase inhibited, inc gluconeogenesis

control by insulin

binding to plasma receptor in DPlation of enzymes by PPPatases

• ACoAClase activated, inc FA Synthesis

• HSL inhibited, decstored fat mobilization, inc stored fats

• PDHase activated, dec gluconeogenesis, inc glycolysis

ACoA carboxylase

cat. rate limiting step of FA synthesis, formation of MCoA

allosterically activated by citrate

acetone

A volatile, non-metabolizable ketone body. It is a byproduct of ketogenesis and is exhaled or excreted in urine.

BHB B hydroxybutyrate

A stable, energy-rich ketone body, interconvertible with acetoacetate. Used as a fuel in peripheral tissues, including the brain during prolonged fasting.

thiolase

Catalyzes the condensation of two acetyl-CoA molecules to form acetoacetyl-CoA, an early step in ketogenesis and also important in β-oxidation.

HMGCoA Rase

Key regulatory enzyme in cholesterol synthesis, not ketogenesis. Converts HMG-CoA to mevalonate. Inhibited by statins.

HMGCoA Lyase

Catalyzes the cleavage of HMG-CoA to acetoacetate and acetyl-CoA during ketogenesis in liver mitochondria.

ACC acetylCoA Carboxylase

Rate-limiting enzyme of fatty acid synthesis. Converts acetyl-CoA to malonyl-CoA using ATP and biotin. Inhibited by palmitoyl-CoA, activated by citrate and insulin.

biotin

A coenzyme (vitamin B7) required by carboxylases like ACC to transfer CO₂ during carboxylation reactions.

FAS fatty acid synthetase

A multi-enzyme complex that performs the repeated addition of malonyl-CoA to a growing fatty acid chain.

ACP

Part of FAS; it holds the growing fatty acid chain and intermediates during elongation.

acyl carrier protein

OA oxaloacetate

Combines with mitochondrial acetyl-CoA to form citrate (via citrate synthase) for transport.

citrate transporter

Transports citrate from mitochondria into cytosol, where citrate is cleaved to release acetyl-CoA and OAA.

malate aKG transporter

Moves malate or α-ketoglutarate across mitochondrial membranes to help regenerate NADPH or shuttle carbon skeletons.

pyruvate transporter

Brings pyruvate from cytosol into mitochondria, completing the cycle for citrate-pyruvate shuttle (OAA + NADH → malate → pyruvate).