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What is the first major step of cholesterol metabolism?
Acetyl CoAs are converted into 3-hydroxy-3 methylglutaryl CoA (HMG-CoA).
HMG-CoA is the precursor for cholesterol synthesis.
Also an intermediate for ketone body synthesis from acetyl-CoA (these are made in the mitochondrial matrix, while HMG-CoA destined for cholesterol is made by different but equivalent enzymes in the cytosol)
What is the second major step in cholesterol metabolism?
HMG-CoA is converted to mevalonate by HMG-CoA reductase.
Carboxyl group of HMG-CoA that is in ester linkage to the thiol of CoA is reduced to an aldehyde and then to alcohol.
NADPH serves as reductant (large biosynthesis, uses NADPH).
What is the third major step of cholesterol metabolism?
Mevalonate is converted to the isoprene based molecule isopentenyl pyrophosphate (IPP).
Mevalonate is phosphorylated by 2 sequential ATP transfers, yielding the pyrophosphate derivative.
ATP dependent decarboxylation with dehydration yields isopentenyl pyrophosphate.
What is the fourth major step of cholesterol metabolism?
Isopentenyl pyrophosphate isomerase inter-converts IPP into dimethylallyl pyrophoshate
What is the fifth major step of cholesterol metabolism?
PRENYL TRANSFERASE (farnesyl pyrophosphate synthase) catalyzes series of HEAD-TO-TAIL CONDENSATION REACTIONS. THESE REACTIONS ADD IPP to dimethylallyl PP to form farensyl pyrophosphate.
What is the sixth major step of cholesterol metabolism?
Squalene synthase catalyzes head-to-head condensation of 2 farnesyl PPs with NADPH reduction to yield squalene
What is the seventh major step of cholesterol metabolism?
Squalene epoxidase catalyzes oxidation of squalene to form 2,3-oxidosqualene (requires NADPH as reductant and O2 as oxidant
What is the eighth major step of cholesterol metabolism?
Squalene oxidocyclase catalzes series of electron shifts that produces sterol, lanosterol
How many reactions does lanosterol undergo to become cholesterol?
19
What is the rate limiting step of cholesterol synthesis and how is it regulated on the short term?
The rate-limiting step for cholesterol synthesis is HMG-CoA reductase conversion of HMG-CoA into mevalonate.
Short-term regulated by phosphorylation catalyzed by AMP-dependent protein kinase (HMG-CoA reductase kinase).
When kinase active, cellular AMP is high and ATP is low
What is the long term regulation of HMG-CoA reductase?
Long-term regulated by the varied formation and degradation of HMG-CoA reductase and other pathway enzymes.
Proteolysis of HMG-CoA reductase (degradation stimulated by cholesterol, oxidized derivatives of cholesterol, mevalonate, and farnesol, which is dephosphorylated farnesyl PP).
Has a transmembrane sterol-sensing domain that has a role in activating degradation of the enzyme.
Describe the action of SREBP-2 and how it interacts with SCAP.
Transcription factor SREBP-2 (sterol regulatory element binding protein #2) responds to cell sterol level.
When low, SREBP-2 released by cleavage of precursor protein in ER membranes.
Then translocates into nucleus where it functions as transcription factor to activate transcription genes for HMG-CoA reductase and other enzymes of the pathway.
SCAP (SREBP cleavage activating protein) is an integral protein of ER membranes that has a transmembrane sterol-sensing domain homologous to that of HMG-CoA reductase. SCAP inhibited by binding of sterols - when sterols low, SCAP binds and transports SREBP precursor from ER to golgi
Protease S1P (site one, serine protease), is an integral protein of golgi membranes that cleaves the SREBP precursor at a particular site in lumenal domain
Protease S2P cleaves within transmembrane segment of SREBP precursor, releasing to the cytosol the N-terminal SREBP protein (which functions as transcription factor). Only S1P cleavage product can serve as substrate for S2P.
Zinc metalloprotease domain within transmembrane region of S2P. catalyzes cleavage within the transmembrane segment of SREBP protein.
How can cholesterol negatively regulation its own synthesis?
By inhibiting SREBP processing by inhibiting SCAP, this leads to inhibition of cholesterol synthesis.
How can farensyl pyrophosphate lead to cancer?
FPP can be converted into gernanylngeranyl pyrophosphate, which can lead to the creation of prenylated proteins, leading to cancer.
What are some characteristics of cholesterol?
Carbon 3 OH group, Carbon 5/6 alkene, and steroid nucleus
Briefly describe the structure of digoxin. What does it do?
Used to treat congestive heart failure.
What are the end products of cholesterol utilization?
Bile acids. Used for the excretion of exces cholesterol (but excretion of cholesterol as bile acids is insufficient to compensate for excess dietary intake of cholesterol).
Most abundant are chenodeoxycholic acid and cholic acid.
Primary bile acids are digested by intestinal bacteria to yield secondary bile acids, deoxycholate and lithocholate.
Both are absorbed by intestines and delivered to liver via portal circulation.
Briefly describe the synthesis of primary bile acids.
What is the relation between circulating (in digestive system) bile and cholesterol?
What are the four physiologically important functions of bile acids?
