LM 2.2: Steroid Synthesis Flashcards
what is the function of cholesterol?
it’s a component of cell membranes that:
1. modulates membrane fluidity and mobility of membrane proteins
- enriched in lipid rafts
- required for membrane replication during cell growth
- it’s the building block of steroid hormone synthesis
how do atherosclerotic plaques form?
- cholesterol is carried by LDL in the blood
- oxidized LDL containing cholesterol esters is taken up by macrophages, which enlarge to become “foam cells”
- foam cells are trapped in blood vessel walls, leading to the formation of cholesterol-rich plaques
as lumen is narrowed by plaque, blood flow is restricted
where does cholesterol come from?
- diet
2. de novo synthesis
what are the building blocks for cholesterol synthesis?
5-carbon isoprene units
cholesterol is formed from acetyl-CoA via a complex branched pathway
cholesterol serves as a precursor for bile acids, steroid hormones and vitamin D
what is the rate limiting step for cholesterol formation?
HMG-CoA reductase
it’s the key target for drug therapy with statins!
what is the pathway to cholesterol synthesis?
acetyl CoA ↓ acetoacetyl CoA ↓ HMG-CoA ↓ mevalonate via HMG-CoA reducatse ↓ isopentenyl-PP ↓ geranyl-PP ↓farnesyl-PP ↓ squalene ↓ cholesterol
levostatin inhibits the HMG-Coa –> mevalonate step by inhibiting HMG-CoA reductase; statins reduce circulating LDL-cholesterol to reduce risk fo CVD
farnesyl-PP can also go another route and form isoprenylated proteins, heme a, ubiquinones and dolichols
where does synthesis of HMG-CoA occur?
cytoplasm
HMG-CoA then serves as a substrate for HMG-CoA reductase in the ER
what are the first 2 steps in the cholesterol synthesis pathway?
2 acetyl-CoA –> acetoacetyl CoA via acetoacetyl-CoA thiolase
acetoacetyl CoA –> HMG-CoA via HMG-Coa synthase
so thiolase combines 2 acetyl-CoA molecules in a condensation reaction to make acetoacetyl-CoA and then acetyl CoA is added in by action of hog-CoA synthase to produce HMG-CoA
how does cholesterol synthesis parallel ketogenesis?
synthesis of HMG-CoA for ketogenesis occurs by a parallel pathway inside the mitochondria
HMG-CoA serves as a substrate for HMG-CoA lyase to produce acetoacetate
when is the de novo cholesterol synthesis pathway activated?
HMG-CoA –> mevalonate via HMG-CoA reductase is only active when cells require de novo cholesterol synthesis
with sufficient dietary intake of cholesterol taken up by the liver as LDL-cholesterol, this de novo pathway is inhibited by reducing HMG CoA reductase levels
regulation of HMG-CoA Reductase plays a key role in cellular cholesterol homeostasis
how do satins regulate cholesterol levels?
statins are competitive inhibitors of HMG-CoA reductase – they bind to the catalytic side of HMG-CoA reductase and inhibit its enzymatic activity which causes a small detectable drop in cellular cholesterol
it’s the circulating LDL that’s out in the blood that is the real source of concerning cholesterol, it’s not so much the cholesterol in the liver
the small block in cholesterol synthesis tricks the cell into thinking they’re cholesterol deprived which results in increased LDL receptor formation and this leads to LDL being taken up from the blood and channeled to the liver where it can be disposed of via the bile-acid pathway
how many carbons are in cholesterols?
from mavalonate to farnesyl pyrophosphate there are 3 different pyrophosphate intermediates: isopentenyl –> geranyl –> farnesyl
5 carbon isoprene units are incorporated in three successive reactions to build up the number of carbons needed for cholesterol formation, starting from the 6 carbon mevalonate – you are going to end with a 15 carbon farnesyl pyrophosphate
what is the intermediate in between squalene and cholesterol in the cholesterol synthesis pathway?
lanosterol
there’s 19 steps between the conversion of lanosterol to cholesterol and some intermediates formed in this process include 7-dehydrocholesterol, which is a precursor for Vitamin D
UV light is needed to convert 7-dehydrocholesterol, into vitamin d3
how do bile salts play a role in cholesterol elimination?
bile salts are polar derivatives of cholesterol that are produced in the liver and stored in the gall bladder
they’re released into the duodenum when fats are present and they aid in emulsifying dietary lipids
most bile acids are reabsorbed in the ileum and reutilized while some are eliminated in the feces with choelsterole
excretion of bile acids is the major pathway for elimination of cholesterol!!
bile acid sequestrates are used to prevent bile acid reabsorption and are used as choelsterol-lowering agents
how do you make bile acids from cholesterol? what are the 2 major bile salts?
the rate limiting step of 7 α-Hydroxylase converting cholesterol to 7-hydroxycholesterol
then there’s a bunch of steps that make chilly-CoA and chenodeoxycholyl-CoA that get condensed with AA to form bile acids/salts!
- cholyl-CoA + glycine –> glycocholate
- cholyl-CoA + taurine –> taurocholate
