Complex Lipid Synthesis and Breakdown Flashcards
(33 cards)
Triacylglycerol and Phospholipid Synthesis - What? Why? Where?
What - Using glycerol as the “backbone,” either 3 fatty acid groups are attached to form TAG OR 2 fatty acid groups plus a headgroup of phosphate and an alcohol form the phospholipids
Why - TAGs are the preferred storage form of fuel in adipose tissue, where they are nearly anhydrous globules in the cytosol of adipocytes
Phospholipids have several functions: major component of membranes (cells, organelles); reservoir for intracellular messengers; anchor some membrane-bound proteins; components of lung surfactants and bile
Where - TAGs: cytosol w/ final step in cytoplasmic face of ER; primarily in adipose and liver tissue (and also lactating mammary glands and intestinal mucosal cells)
Phospholipids: smooth endoplasmic reticulum - then to Golgi, various membranes, or secreted via exocytosis; occurs in all cells (except mature RBCs)
Triacylglycerol and Phospholipid Synthesis - How?
Primary pathway for TAG and phospholipid synthesis is called de novo pathway & can be divided into four main steps
- Backbone synthesis: glycerol 3-phosphate formed
- two fatty acids attached -> Phosphatidate
- To form TAG - phoshpate group is removed from phosphatidate and a third fatty acid is attached to C3
- OR to form phospholipids - phosphatidate is activated by CTP addition to form CDP-diacylglycerol and appropriate alcohol headgroups attached
Draw the pathway of Triacylglycerol and Phospholipid Synthesis
Sphingomyelin and Glycolipid Synthesis - What? Why? Where?
What - Using sphingosine as a backbone, a fatty acid is attached through an amide bond to C2 to form ceramide; For sphingomyelin, a phosphorylcholine is attached to C1; Glycolipids have one or more sugars attached to C1 (but NO phosphate group)
Why - Sphingomyelin is an important component of the myelin of nerve fibers; Glycolipids are structural components of membranes (particularly nerve tissues) and generate lipid-signaling molecules, like phospholipids can
Where - Endoplasmic Reticulum and Golgi apparatus
Sphingomyelin and Glycolipid Synthesis - How?
- Formation of sphingosine: synthesis of the backbone
- Ceramide formation: attache fatty acid via amide bond to C2
- Form sphingomyelin (using CDP-choline) OR
- Form glycolipids - attaching one or more sugars as polar head group
Draw the pathway of Sphingomyelin and Glycolipid Synthesis
Phospholipid and Sphingolipid/Glycolipid Degradation Pathways - What? Why?
What - the breakdown of phospholipids - either completely or ‘partially’ - to yield various fatty acids, alcohol headgroups, glycerol, etc
Why - membrane PL degradation plays important role in signaling: Arachidonic acid -> released by phospholipase A2 -> prostaglandin synthesis; IP3 and DAG -> released by phospholipase C (from phosphorylated phosphatidyl inositol); both are second messengers in signaling pathways
Continuous turnover in membranes to remove/replace oxidized lipids produced by ROS such as O2 and H2O2
Result: oxidized (broken) lipid -> leaky membrane
To alter the membrane composition to maintain proper fluidity or other membrane functions;
Where - many of the enzymes are in or associated with membranes in all cells
Phospholipid and Sphingolipid/Glycolipid Degradation Pathways - How?
Numerous specific phospholipases (PLA2, PLC, etc) which remove FA tails or headgroups; and glycosidases, which remove the sugar headgroups of glycolipids
Clinical problems due to defects in lipid synthesis and degradation pathways
Obesity - apparent genetic contributions, as well as environmental and behavioral factors
Lipid storage diseases - due to defects in phospholipid or sphingolipid degradation
Sphingolipid Storage Diseases of Humans - Tay-Sachs disease
Principal storage substance: Ganglioside G
Enzyme deficiency: Hexosaminidase A
Sign/symptoms: Mental retardation, blindness, cherry red spot on macula, death between second and third year
Sphingolipid Storage Diseases of Humans - Gaucher’s disease
Storage substance: Glucocerebroside
Enzyme deficiency: Glucocerebrosidase
Signs/Symptoms: Liver and spleen enlargement, erosion of long bones and pelvis, mental retardation in infantile form only
Sphingolipid Storage Diseases of Humans - Fabry’s disease
Storage Substance: Ceramide trihexoside
Enzyme deficiency: alpha-Galactosidase A
Signs/Symptoms: Skin rash, kidney failure, pains in lower extremities
Sphingolipid Storage Diseases of Humans - Niemann-Pick disease
Storage Substance: Sphingomyelin
Enzyme deficiency: Sphingomyelinase
Signs/Symptoms: Liver and spleen enlargement, mental retardation
Sphingolipid Storage Diseases of Humans - Globoid leukodystrophy (Krabbe’s disease)
Storage substance: Galactocerebroside
Enzyme deficiency: Galactocerebrosidase
Signs/Symptoms: Mental retardation, absence of myelin
Sphingolipid Storage Diseases of Humans - Metachromatic leukodystrophy
Storage Substance: Sulfatide
Enzyme deficiency: Arylsulfatase A
Signs/Symptoms: Mental retardation, nerves stain yellowish brown with cresyl violet dye (metachromasia)
Sphingolipid Storage Diseases of Humans - Generalized gangliosidosis
Storage substance: Ganglioside Gmi
Enzyme deficiency: Gmi ganglioside: beta-galactosidase
Signs/Symptoms: Mental retardation, liver enlargement, skeletal involvement
Sphingolipid Storage Diseases of Humans - Sandhoff-Jatzkewitz
Storage substance: Gm2 ganglioside, globoside
Enzyme deficiency: Hexosaminidase A and B
Signs/Symptoms: Same as 1; disease has more rapidly progressing course
Sphingolipid Storage Diseases of Humans - Fucosidosis
Storage Substance: Pentahexosylfucoglycolipid
Enzyme deficiency: alpha-L-fucosidase
Signs/Symptoms: cerebral degeneration, muscle spasticity, thick skin
Respiratory Distress Syndrome
Premature babes develop RDS because of immaturity of their lungs resulting from a deficiency of pulmonary surfactant
Maturity of fetal lung can be predicted antenatally by measuring lecithin/sphingomyelin (L/S) ratio in the amniotic fluid
Critical L/S ratio is 2.0 or greater
risk of developing RDS when L/S ratio is < 2.0
Results unreliable if amniotic fluid specimen has been contaminated by blood or meconium
Determination of saturated palmitoylphosphatidylcholine (SPC), phosphatidylglycerol, and phosphatidylinositol have been found to be additional predicotors of RDS
Exogenous surfactant replacement therapy using surfactant from human and animal lungs is effective in prevention and treatment of RDS
Cholesterol Synthesis - What? Why? Where?
What - use of 18 acetyl CoAs (2C units) to make cholesterol - a 27C, 4 ring structure
Why - Cholesterol is an essential component of membranes and is a precursor to steroid hormones and bile salts; can also be used to make Vitamin D
Where - Cytosol (and smooth ER for latter part of pathway) of all cells; NOT a dietary requirement
Cholesterol Synthesis - How?
Overall reaction:
18 acetyl CoA + 18 ATP + 14 (NADPH + H+) + O2 –> 1 cholesterol (27 carbons) + 18 (ADP + Pi) + 14 NADP+
Overview of cholesterol synthesis pathway:
Draw the pathway of Cholesterol Synthesis
Regulation of Cholesterol Metabolism - HMG-CoA Reductase
Catalyzes the committed step of cholesterol synthesis; thus major control point
Reaction: HMG-CoA -> mevalonate (redox reaction)
Phosphorylation state of HMG-CoA reductase: Phosphorylated HMG-CoA reductase is inactive; Dephosphorylated HMG-CoA reducatse is active
Four levels of regulation of HMG-CoA reductase: Hormonal regulation (outside cell); Regulation of gene expression of the enzyme; Regulation of protein breakdown of the enzyme; Inhibited by cholesterol, a cellular effector
Hormonal regulation: Insulin (+): activates a phosphatase to dephosphorylate HMG-CoA reductase -> activation; Glucagon (-): activates a kinase to phosphorylate HMG-CoA reductase; thus is inactivated
Regulation of gene expression of the reductase: Cholesterol (-): HMG-CoA reductase synthesis
Regulation of protein breakdown of the reductase: Cholesterol (+): HMG-CoA reductase degradation; ultimately a NEGATIVE EFFECT on cholesterol synthesis since removing enzyme from cell
Regulation of Cholesterol Metabolism - Synthesis of the LDL receptor is also regulated
Cholesterol (-): LDL receptor synthesis
LDL primarily carries cholesterol, so if enough cholesterol, do not want to endocytose an LDL
