Cholesterol and Ketone Body Metabolism

A set of 16 vocabulary flashcards covering essential enzymes, intermediates, and processes involved in cholesterol synthesis and ketone body metabolism.

Cholesterol synthesis location

Occurs in the cytosol of the brain, intestines, ovaries, and testes

Statins

Competitive inhibitors of HMG-CoA reductase to prevent cholesterol synthesis; mimic mevalonate

ACAT (Acyl-CoA:cholesterol acyltransferase)

ER enzyme that esterifies cholesterol with fatty acyl-CoA to form cholesteryl esters for storage or lipoprotein packaging.

Ketone Bodies

Used for CAC by oxidation into acetyl-CoA; created but not used in the liver. Includes acetoacetate, acetone (not used, breathed out), and D-B-hydroxybutyrate

Acetoacetate

Primary ketone body formed from 2 Acetyl-CoA; can be reduced to D-β-hydroxybutyrate or turned into acetone via spontaneous (non-enzymatic) decarboxylation.

Cholesterol synthesis step 1: Condensation. Not favorable, but pulled by rapid use of HMG-CoA

2 Acetyl-CoA → (via acetyl-CoA acetyl transferase) Acetoacetyl-CoA + CoA-SH + Acetyl-CoA → (via HMG-CoA synthase) B-hydroxy-B-methylgutaryl-CoA (HMG-CoA) + CoA-SH

Cholesterol synthesis 2: committed step

HMG-CoA + 2 NADPH + 2 H+ → (via HMG-CoA reductase) Mevalonate + 2 NADP+ + CoA-SH

Cholesterol Synthesis 3: Addition of phosphates one at a time using ATP

Mevalonate + ATP → (via mevalonate 5-phosphototransferase) 5-Phosphomevalonate + ADP + ATP → (via phosphomevalonate kinase) 5-pyrophosphomevalonate + ADP + ATP → (via pyrophosphomevalonate decarboxylase) 3-phospho-5-pyrophosphomevalonate + ADP

Cholesterol synthesis 4: interconversion of two isoprenes

3-phospho-5-pyrophosphomevalonate → (via pyrophosphomevalonate decarboxylase) delta3-isopentenyl pyrophosphate (IPP)+ Co2, Pi (leave) → (via isopentenyl pyrophosphate isomerase) dimethylallyl pyrophosphate (DMAPP) (interconverts between the two activated isoprenes)

Cholesterol synthesis 5: condensation of 6 activated isoprene units

DMAPP + IPP → (via prenyl transferase, head-to-tail condensation) Geranyl pyrophosphate (10-C molecule) + PPi (leaves) + IPP → (via prenyl transferase) Farnesyl pyrophosphate (15-C molecule, FPP) + PPi (leaves) + another FPP + NADPH + H+ → (via squalene synthase) squalene (30-C molecule) + NADP+ + 2 PPi (leave)

Cholesterol synthesis 6:

squalene + NADPH + H+ + O2 → (via squalene monooxygenase) squalene 2,3-epoxide + H2O + NADP+

Cholesterol synthesis 7:

animals: Squalene 2,3-epoxide → (via cyclase) Lanosterol → (19 steps that remove 3 C, move double bonds) → Cholesterol

Squalene 2,3-epoxide fat for plants + fungi

plants: squalene 2,3-epoxide → stigmasterol; fungi: squalene 2,3-epoxide → ergosterol

metabolic fates of cholesterol

hydrosterols, steroid hormones, bile acids, cholesteryl ester (via acyl-CoA-cholesterol acyltransferase + addition of fatty acyl-CoA)

ketogenesis

occurs in mitochondria

1. 2 acetyl-CoA → (via thiolase) Acetoacetyl-CoA + CoA-SH

2. Acetoacetyl-CoA + Acetyl-CoA → (via mitochondrial HMG-CoA synthase) HMG-CoA + CoA-SH

3. HMG-CoA → (via liver mitochondria HMG-CoA lyase) Acetoacetate + Acetyl-CoA

4. Acetoacetate → acetone or D-B-hydroxybutyrate (via D-B-hydroxybutyrate DH)

ketone body oxidation

occurs in target organs

1. D-B-hydroxybutyrate + NAD+ → (via D-B-hydroxybutyrate DH) Acetoacetate + NADH + H+

2. Acetoacetate + Succinyl-CoA → (via Succinyl-CoA:acetoacetate CoA transferase) Acetoacetyl CoA + Succinate

3. Acetoacetyl CoA + CoA-SH → (via thiolase) 2 Acetyl-CoA