Fatty Acids
Fatty acrids are carboxylic acids composed of a hydrocarbon chain
Most lipids contain fatty acids or are derived from fatty acids
Storage Lipids
Fatty acids are esterified to glycerol, forming triacylglycerols
- Triacylglcerol contains a single glycerol molecule linked to three fatty acids.
- Adipocytes store large amounts of triacylglycerols as fat droplets that nearly fill the cell.
- Lipases are enzymes that release the fatty acids, which are subsequently oxidized to yield energy.
Biological Membranes - Cardiolipin and Barth syndrome
Cardiolipin is a phospholipid particulary abundant in mitochondria where it is required for optimal function of numreous enzymes involved in mitochondrial energy metabolism
In Barth Syndrome, infantile death occurs due to deficient cardiolipin synthesis. Decreased mitochondrial ATP productions –> cardiomyopathy and general weakness
Asymmetric distribution between the two monolayers of the bilary
Phosphatidylserine is found on the inner monolayer of the plasma membrane - facing the cytoplasm
Phospholipids - Glycerophospholipids
Phospholipids are constructed on glycerol bckbone except that PO4 is esterified at C3 instead of fatty acid
- Phosphatidic acid is the parent compound from which other phospholipids can be synthesized by modificaiton of PO4 group
- Linked to highly polar or charged “head group” by a phosphodiester linkage
- Majority have a net negative charge at ph7
- PE and PC are neutral at pH7
Phosphatidic Acid (PA) Synthesis
PA is formed by adding two fatty acids onto glycerol-3-phosphate by acyl transferases
- Glycerol 3 Phosphate is primarily derived from reduction of the glycolytic intermediate, dihydroxyacetone phosphate
Fatty Acid Incorporation
1) Triacylglycerols for the storage of metabolic energy
2) Phospholipd components of membrane
Partitioning is dictated by the body’s needs. In times of rapid growth, synthesis of new membranes requires production of membrane phospholipds, and in times of abundant food supply and non active growth periods, mostly fatty acids are shunted into triacylglycerols for storage of metabolic energy.
Alternative PA Synthesis
1) Phosphorylation of diacylglycerol (DAG) by DAG kinase
2) Phospholipase D-mediated hydrolysis of phosphatidylcholine
Phosphate Group in Phosphatides
The phosphate group is supplied by cytidine diphosphate (CDP). The second most important role for CTP (after nucleic acid synthesis) is phospholipid biosynthesis.
Pulmonary Surfactant
Surface forces in alveolar structs are countered by pulmonary surfactant that reduce surfice tension
- Surfactant is synthesized and secreted by alveolar type II epithelial cells
- forms a film covering the cells
- Deficiency is the primary cause of neonatal respiratory distress syndrome (RDS) and surfactant supplementation in premature infants with RDS significiantly reduces mortality in these patients
Pulmonary surfactant is a complex mixture of lipids and proteins with dipalmitoylphosphatidylcholine (DPCC) being the most abundant and phosphatidylglycerol being the second most abundant phospholipid.
Lipids constitute ~90% of the composition
Phosphatidylserine (PS)
Change in the distribution of PS to the outside of the plasma membrane marks a cell as dying and undergoing a process called apoptosis
- In a healthy, living cell, PS is vastly in the inner monolayer
Phospholipases
Specifically cleave phospholipids and are involved in phospholipid remodeling and intracellular signaling
- Phospholipase A1 remove fatty acids from C1
- Phospholipase A2 removes fatty acids from C2
- Permits re-esterificaiton with other fattyl acyl CoAs or release of arachidonic acid (from C2)
- Phospholipase C and D cleave teh C3 phosphodiester to produce either DAG or Phosphatidic acid, respectively.
Phosphatidylinositols (PIs) and Cell Signaling
Phospholipase C cleaves Phosphatidylinositol 4,5 bisphosphate (PIP2) to produce two products that are active in signaling
- Diacylglycerol (DAG)
- Inositol 1,4,5-triphosphate (IP3)
- soluble and triggers release of Ca++ from the ER.
- Combines with DAG which stays in cell membrane to activate protein kinase C (PKC).
Membrane-associated Proteins
Glycosyl Phosphatidylinositol (GPI) anchor allows proteins to attach to extracellular membrane
- Peripheral proteins with covalentyl attached lipid
Ether Phospholipids - Platelet-activating factor (PAF)
PAF induces platlet aggregation and the release of serotonin (vasocontrictor) from platelets, and stimulates smooth muscle contraction.
Also mediates hypersensitivity and anaphylactic shock.
- Causes these effects by binding to an extracellular receptor on target cells
Sphingolipids
Particularly abundant in cells of the CNS
Like phospholipds, they contain a polar head group and two nonpolar tails, however sphingolipids do not contain glycerol, but one molecule of the long-chain amino alcohol, sphingosine.
When a fatty acid is attached to the amide group at C2 of sphingosine, the resulting comound is a ceramide, which is structurally similar to diacylglycerol.
*Ceramide is the base compound of the sphingolipids (like phosphatidic acid is of phospholipids)
Sphingomyelins
contain phosphocholine as their polar group
No net charge on their polar head group at ph 7
especially abundant in myelin, the membranous sheath that surrounds and insulates the axons of some neurons
Gangliosides
The most complex sphingolipids with polar groups comprised of oligosaccharides with one or more N-acetylneuraminic acid.
- Neu5Ac is a sialic acid and gives gangliosides a negative charge at pH7
- found at highest concentration in the nervou system, particularly the gray matter of the brain
Lysosomes
Phospholipids and Sphingolipids are degraded in lysosomes by the action of hydrolytic enzymes, including phospholipases.
Degradation of sphingolipids produces sphingosine and fatty acids
Lysosomal Storage Diseases
Occur when hydrolytic enzymes are compromised causes the substrate to accumulate in the lysosomes of tissues responsible for its catabolism
Tay-Sachs and Niemann-Pick both caused by abnormal accumulation of spingolipids
- exhibit severe neurological defects
Eicosanoids
Fatty acid derivatives that are short-lived
Family of paracrine hormones that act as short-range singaling molecules , affecting tissues near the cells that produce them.
- Mediate their effect by interacting with cell surface G-protein coupled receptors
Eicosanoids - 3 Classes
- Prostaglandins (5 membered ring)
- Thromboxanes (6 membered ring)
- Leukotrienes (no ring)
All eicosanoids are synthesized from arachidonic acid
- Precursor is linoleic acid (required in diet as essential fatty acids)
- component of membrane phospholipids which make it ready available for eicosanoid synthesis following phospholipid A2 cleavage
Cyclooxygenase Pathway
Cyclooxygenase (COX) cyclyzes and oxidizies arachidonic acid
- composed of cyclooxygenase and glutathione-dependent peroxidase activites
- COX-1 is constitutively expressed in many tissues
- COX-2 exhibits inducible expression in selected cell types
Thromboxanes are synthesized from PGH2 by thromboxane syntahse in platelets that converts teh cyclopentane ring into a 6 membered oxygen containing (oxane) ring.
Leukotrienes
Linear molecules with 4 double bonds (3 in serines forming a triene)
- Arachidonic acid is converted to leuoktrienes by lipoxygenases (forming a -OOH_ group on the molecule
- Major leukotrienes produced by 5-lopoxygenase
