Eicosanoids and prostaglandins

Question 1

Eicosanoids are C20 lipid hormones often derived from arachnidonic acid

Answer 1

Arachidonate: stored in phospholipids as a C2 ester of phospholipids, released by phospholipase A2
Arachidonic acid is a C20 fatty acid
Polyunsaturated: all cis-5,8,11,14-eicosatetraenoic acid
Also an omega-6 fatty acid

Question 2

Prostaglandins are eicosanoids

Answer 2

Locally acting (non-circulating hormones)
Often synthesized and released in response to other hormones
Pain, inflammation, fever

Question 3

COX-2 Inhibitors for inflammatory diseases

Answer 3

COX-2 specific inhibitors designed to target inflammation w/o side effects (Eg. gastric)
Vioxx withdrawn for unrelated (Cardiovascular) side effects in many countries

Question 4

Cholesterol is synthesized from

Answer 4

Acetyl-CoA

Cholestrol: Most animal cells can syn cholesterol
20-25% made in liver
Precursor to bile salts
Precursor to steroid hormones

Question 5

4 major parts of cholesterol syn

Answer 5

1. Synthesis of mevalonate (C6) from acetyl-CoA (C2) by way of HMG-CoA (C6)
2. Formation of Isopentenyl Pyrophosphate (C5, isoprene unit) from mevalonate
3. Successive condesaations to form C5–> C10–>C15–>C30 Squalene
4. Squaline cyclisation to yield cholesterol in 21 steps!

Question 6

*1: Isoprene is a common unit of cholesterol biosynthesis

Answer 6

5 C unit

6 isoprene units are condensed to form squalene (C30) an acyclic molecule

Question 7

*2: HMG-CoA reductase is the rate-limiting step

Answer 7

4 steps to convert HMG-CoA to Isopentenyl pyrophosphate

1st step produces mevalonate (c6) by HMG-CoA reductase (Rate-limiting)

Question 8

Synthesis of cholesterol and cholesterol esters

Answer 8

Squalene–(many steps)–>cholestrol—-(acyl-CoA cholesterol acyltransferase [ACAT] in liver )–> Cholesteryl ester

Question 9

Maintenance of intracellular cholesterol homeostasis

Answer 9

Short term
-lower activity of HMG-CoA reductase
Long term
-Reduce LDL receptor
-Increase ACAT synthesis
-Control amt of HMG-CoA reductase

Question 10

Control of cholesterol biosynthesis by cholesterol

Answer 10

Enzyme lvls can change up to 200fold
Genes for cholesterol biosyn enzymes and LDL receptor contain Sterol regulatory binding element (SRE)
Binding of SRE to SREBP is required for trspn
Inactive SREBP is housed in ER with SCAP (cleavage activating ptn)
SCAP escorts and facilitates release of SREBP when cholesterol is low