Phospholipids and Glycolipids

Phospholipids are important components of membranes and serum lipoproteins; they also serve as a source of signalling molecules called prostaglandins

Phospholipid Synthesis – two distinct pathways

(1) De Novo Pathway – addition of activated diacylglycerol to head group

starts with phosphatidic acid (diacylglycerol phosphate)
activate by addition of cytosine CTP – forms CDP-diacylglycerol (activated, like UDP-glucose)
replace CMP with a "head group" alcohol such as serine or inisitol
serine can be decarboxylated to ethanolamine, which can be trimethylated (from one carbon pool) to choline (a tertiary amine) - lecithin

(2) Salvage Pathway – addition of activated head group to diacylglycerol

starts with head group (usually choline or ethanolamine – from diet or breakdown of phospholipids)
activate by addition of cytosine – forms CDP-choline (-ethanolamine, etc.)
replace CMP with diacylglycerol

Hydrolysis of Phospholipids – done by phospholipases

There are four types of phospholipases, named for their specificity; induce water Þ hydrolyze

(1) Phospholipase A₁ – cleaves terminal acyl group (at C-1)

(2) Phospholipase A₂ – cleaves middle acyl group (at C-2)

arachadonic acid is usually at C-2 – A₂ is thus the committed regulatory step in prostaglandin synthesis

(3) Phospholipase C – cleaves head group before phosphate, producing diacylglycerol and a phosphorylated head group

essentially "salvage pathway in reverse"
important for formation of inisitol phosphate, a signalling molecule as important as cAMP

(4) Phospholipase D – cleaves head group after phosphate, producing head group and phosphatidic acid (diacylglycerol phosphate)

essentially "de novo pathway in reverse"
important for signalling

Prostaglandins, Leukotrienes, and Thromboxanes

Prostaglandins are formed from cleavage of arachadonic acid from membrane phosphlipids to produce prostanoic acid

have five-membered ring – produced through peroxide intermediate (molecular O₂ added) by cyclooxygenase (COX)

COX-I produces prostaglandins that mediate coagulation; COX-II mediates inflammation
COX-II is a good pharmacological target for prevention of inflammation (aspirin, ibuprofen) – but inhibit COX-I too

short-lived signalling molecules (degraded in seconds to minutes); also not very water soluble – do not go far
important as mediators of inflammation

Thromboxanes – produced through same pathway as prostaglandins – anticoagulation effects (COX-I)

Leukotrienes – also from arachadonic acid – straight chain, mediate inflammation – act locally

Sphingolipids and Glycolipids

Sphingosine - long hydrophobic tail; ceramide (found in all mature membrane sphingolipids) has two tails (like DAG):

(1) Sphingomyelin – ceramide with phosphocholine head group – major component of plasma membrane

(2) Glycolipids – lipids with carbohydrate adducts – e.g., ceramide + sugar – synthesized by glycosyl transferases in Golgi

most common: gangliosides (contain sialic acid), also ABO blood type (A = GalNAc, B = Gal, O = neither)
found mostly on plasma membrane, facing extracellular space – especially in neuronal and epithelial cells
mediate cell-cell recognition and communication, also control division and differentiation
degraded in lysosomes by specific enzymes

lysosomal storage diseases (I cell disease) result from deficiency of enzymes to degrade them (due to lack of mannose-6-P tag) – mental retardation

Peroxisomes – produce ether glycerolipids (plasmalogens)

Plasmalogens make up 30% of most cell membranes, 80-90% of myelin

three enzymes are involved – if any are missing, severe mental problems result
Zellweger Syndrome – no peroxisomes – death in infancy due to severe neural problems