Where in the body is cholesterol made?
in the liver, in the cytosol of the cells
also made in intestines, adrenals, gonads, skin, neural tissue and aorta???
What molecule provides all the carbon atoms of cholesterol?
acetate
What cofactor provides the reducing equivalents for the synthesis?
NADPH
acetyl Coa-->-->beta hydroxy beta methyglutaryl CoA (HMG CoA)-->mevalonate
mevalonate-->isopentenyl pyrophosphate (IPP) and 3,3 dimethylallyl pyrophosphate (DPP)
mevalonate is activated (phosphorylated) then carboxylated (needs biotin)
IPP and DPP are isoprenoid isomers
IPP and DPP condense-->squalene-->lanosterol-->chole
Which molecule is this one?
squalene
a triterpene
specific gravity of 0.855
this is the molecule that gets "cyclized" to form rings-->steroid synthesis
has been used as an adjuvant in vaccines (incr immune response) (CMV vaccine)
some veterans say it causes Gulf War Syndrome (study published 2002, use discontinued Oct 04)
double bonds usually saturated-->squalane for stability in personal care products
What is the source for commercial squalene?
shark liver oil
What are other sources?
amaranth seed, rice bran, wheat germ, olives
Which step is the rate limiting one in cholesterol synthesis?
conversion of HMG CoA to mevolonate
What's the rate limiting enzyme?
HGM CoA reductase
What inhibits this enzyme?
presence of cholesterol from any source (endogenous or dietary)
Is free cholesterol in a cell esterified?
no, but it is in the plasma and in the endosomes
How does HDL get cholesterol out of cells???
binds to its receptor on cell (apo-A-1)-->protein kinase C stims transloc of chol to memb
NOTES FROM BIOCHEMI REVIEW
How do you get acetyl CoA out of the mitochondria??
acetyl CoA goes into TCA, joins OAA to make citrate (synthase)
citrate is transported out of mito via special transporter
citrate lyase splits 2C off, back to acetyl CoA and OAA
the rest of these rxns occur in cytosol
How many acetyl CoA's are joined to make HMG CoA?
Acetyl CoA x2 = acetoacetyl CoA
add one more acetyl CoA to make HMG-CoA (6C)
hydroxylmethylglutaryl CoA (gluta = 6C) is an ester
HMG CoA is reduced twice to form what?
mevalonate
uses 2 NADPH
uses HMG-CoA reductase
loose CoA and ketone in the two reductions
What inhibits HMG-CoA reductase?
easy one
statins don't stop the enzyme's manufacture, rather are competitive inhibitors
they are structural analogs
from wiki: Inhibition of this enzyme in the liver results in decreased cholesterol synthesis as well as increased synthesis of LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream. The first results can be seen after one week of use and the effect is maximal after four to six weeks.
How many ATP does it take to make Isopentenyl pyrophosphate from mevalonate?
2, and you loose CO2 and Pi
C5 = isoprene unit
Two isopentenyl pyrophosphates condense to make what?
geranyl phyrophosphate (C10)
then add one more isoprene
Fearneyl phyrophosphate = 15C
put two of those together to get SQUALENE (30C)
use a cyclase to make LANOSTEROL
that converts to Cholesterol
What is cholesterol used for?
steroids
bile salts
How many isoprene units are contained in cholesterol?
six
How many acetyl CoA's are used in making one cholesterol molecule?
18
loose CO2 that's why there's more
also use 18 ATP
What stimulates cholesterol manufacture in body?
regulated by HMG-CoA enzyme
insulin dephosphorylates enzyme thus activating it
(glucagon phosphorylates via a kinase, and deactivates HMG CoA)
Where is HMG CoA located in cell?
in smooth ER of cytosol
bile and chol inhibit DNA manufacture of mRNA for what??? HMG CoA??
research says pts w/ high chol have low vit C ???
What compound is the basis for CoQ10 synthesis?
mevalonate