Lecture 16 (3-19): Ch. 24 Flashcards
Phosphatidic Acid research application
- phosphatidic acid may act as a target molecule for anti-cancer drugs
- initially synthesized for a drug against anxiety but unsuccessful -> now may offer cancer treatment
Biosynthesis of Other Lipids: Cardiolipin (+ clinical significance)
- present in metabolically active cells of the heart and skeletal muscle
- a “double” phospholipid (it has four fatty acid tails)
- serves as an insulator and stabilizes protein complexes in the ETS
- plays a major role in mitochondrial biogenesis and function
Clinical significance: Barth syndrome
- a rare genetic disorder recognized in 1970s to cause infantile death
- a mutation in the gene coding for the enzyme synthesizing cardiolipin
- sufferers have mitochondria that are abnormal, and cannot sustain adequate production of ATP
Biosynthesis of Other Lipids: Importance of Ceramide
- Ceramide is a key precursor for complex lipids
Sphingolipids:
- if glycosylated -> get cerebrosides
- cerebrosides + silica acid -> get gangliosides
Function (of sphingolipids?):
- component of neural tissues, membrane stabilized
- immune recognition (ABO), toxin recognition (cholera)
Glycosphingolipids:
- Shingomyelin: Lecithin/Sphingo (L/S) ratio - need enough lecithin in lungs for baby to breath (if you don’t have enough, have to stop labor)
- abnormal in Tay-Sachs disease
Biosynthesis of Other Compounds: Eicosanoids
Arachidonic acid: a precursor released by phosphlipase A2 (PLA2)
- generates a family of compounds including:
- – prostaglandins (isolated from human semen in 1930s, they thought they had come from the prostate gland, hence the name)
- – thromboxanes
- – leukotrienes
- – hydroxyeicosanoic acids
Source of name of arachidonic acid: Spiders
- brown recluse venom, is cytotoxic/hemolytic
- it contains hyaluronidase, deoxyribonuclease, ribonuclease, alkaline phosphatase, and lipase and sphingomyelinase D
- Sphingomyelinase D responsible for most of the tissue destruction and hemolysis
- The intense inflammatory response mediated by arachidonic acid, prostaglandins, and chemotactic infiltration of neutrophils
Cholesterol Biosynthesis: overview/discovery (location, importance)
- occurs primarily in the liver
- dominant steroid in animal cells
- critical component of cell membranes
- non-trivial synthesis
- most puzzling was getting to isoprene from 2C units
- squalene structure needed to precede the ringed structure
Cholesterol Biosynthesis: overview of the steps in the first portion of it
- Biosynthesis in the cytosol (of the liver) begins with two Claisen condensations by two enzymes
- First step is a thiolase reaction
- Second step uses HMG-CoA synthase to make HMG-CoA (3-Hydroxy-3-MethylGlutaryl-CoA)
- Third step: HMG-CoA reductase (makes MEVALONATE)
- Note: 2 NADPH reactions
Cholesterol Biosynthesis: second portion of it
- mevalonate –> squalene (note energy consumption)
- squalene –> cholesterol
- cholesterol –> cholesterol ester (requires another Ac-CoA)
- Note: difference between cholesterol and cholesterol ester
Difference between cholesterol esters and cholesterol
- cholesterol esters more efficiently transport dietary and synthesized cholesterol
- free cholesterol is confined to the outer surface of the lipoproteins
- BUT cholesterol esters can be packaged into the interior of lipoproteins
general cholesterol biosynthesis pathway
Acetyl CoA + Acetoacyl CoA ——- (HMG-CoA synthase)—–> HMG-CoA —– (HMG-CoA reductase)——> mevalonate —–> ………. ——> Squalene —-> Cholesterol
Cholesterol Biosynthesis: most common inhibitors
Most common HMG-CoA reductase inhibitors:
- statins: (Pravastatin - brand name Pravachol), (Simvastatin - brand name FloLipid Zocor)
- binding site interaction with rosuvastatin
- tetrahedral intermediate is KEY
Steroid Hormone Synthesis: types + their importance
Cholesterol is a key precursor to a number of compounds (steroids)
- Pregnenolone: formed by desmolase in the mitochondria, migrates to ER where progesterone is formed
- Progesterone is a branch point - it produces sex steroids (testosterone and estradiol/ESTROGEN) and corticosteroids (cortisol and aldosterone)
- —– estrogen related breast cancer (1/8 women in US, 5 year survival about 85%)
- —– progesterone precursor to glucorticoids
- —– progesterone produces mineralocorticoids including aldosterone
- Serve key physiological functions
- Also some undesirable less understood roles - CANCER
- cholesterol also a precursor for bile salts (charged steroids that emulsify fats)
Aldosterone: definition + function
a mineralocorticoid produced from progesterone which cholesterol is a key precursor for
Aldosterone:
- acts on the kidney promoting the reabsorption of sodium ions (Na+) into the blood. Water follows the salt and this helps maintain normal blood pressure
- also acts on sweat glands to reduce the loss of sodium in perspiration
- also acts on taste cells to increase the sensitivity of taste buds to sources of sodium
Biosynthesis of Bile Acids (+ importance of bile acids)
carboxylic acid derivatives of cholesterol (cholesterol is precursor for bile acids)
- essential for the digestion of food, especially for solubilization of ingested fats
- synthesized from cholesterol
- chalice acid conjugates with taurine and glycine to form taurocholic and glycocholic acids
Body as a cholesterol thermostat: Sources of Cholesterol
Synthesized: (in addition to diet -> 25%)
- liver: 25%
- remainder: intestines, adrenals, and reproductive organs
Other effectors:
- supplements? (omega-3’s)
- fiber
- exercise
Anticholesterol approaches
Fat substitutes:
- replace most, if not all, of the fat in a food
- reduce a food’s fat and calories while maintaining the texture provided by fat
- most contain fewer calories than fat, but don’t withstand the cooking temperatures that natural fats do
Prevent Absorption:
- absorption blockers
- bile acid sequestration
Inhibit Select Enzyme Activities:
- regulatory enzymes
Cholesterol substitutes
Cellulose-based:
- Avicel: a cellulose gel introduced in the mid-1960s by FMC Corp.
Dextrin-based:
- N-Oil: a tapioca dextrin introduced in the early 1980s by National Starch and Chemical Co. (these are used in lunch meats, salad dressings, frozen desserts, table spreads, dips, baked goods, and candy)
Protein-based (1990s) - two that are “GRAS” (generally recognized as safe - not toxic, doesn’t cause birth defects, won’t interfere with nutrition, no effect for allergic ppl):
- Microparticulated protein from egg white or dairy protein
- Whey protein concentrate
- (Microparticulation is a process where the protein is shaped into microscopic round particles that roll easily over one another. These fat substitutes give a better texture than the CHO-based ones and can be used in some cooked foods but are not suitable for frying)
Fat-based:
- Olestra: sucrose/fatty acid combination
- has properties similar to those of a naturally occurring fat
- no calories or saturated fat BECAUSE IT IS UNDIGESTIBLE
- tastes ok and passes through the GI tract….but is not absorbed into the body
Problems with cholesterol substitutes
- We need some fat in our diet (essential fatty acids)
- Potential effect on the gastrointestinal system if they are not absorbed?
- Potentially affects absorption of fat-soluble vitamins? other fats?
- Possibly interfere with absorption of other nutrients or drugs?
- What effects might they have in people with conditions that affect nutrition such as intestinal disease? Celiac, IBD, Crohn’s?
- In 1987, Procter and Gamble sought approval to use OLESTRA in salty- or sharp-tasting snacks, such as potato chips, cheese puffs, crackers
- FDA’s Center for Food Safety and Applied Nutrition (CFSAN) explored and approved olestra.
Olestra
- anticholesterol approach
- fat substitutes mimic the molecular shape of fat - one molecule of glycerol/3 FAs
- Olestra: sucrose and has 6-8 adducted FAs (from vegetable oils) - With this many fatty acids, digestive enzymes can’t get to the sucrose center in the time it takes for the substance to move through the digestive tract! Clever! Fake Fat!
- P&G sought FDA approval for olestra - as a drug in 1975 (denied- ineffective reduction of cholesterol)
- In 1987, P&G filed for the approval of the use of olestra as a calorie-free replacement for fat in shortening and cooking oil
- In 1990, granted right to use olestra as 100% replacement for conventional fats in snacks
The fake fat:
- the fat molecule is easily broken down by intestinal enzymes which clamp onto and cleave off two of its three fatty acids from the glycerol backbone. These enzymes cannot grapple with olestra, though, whose many-armed sucrose backbone supports eight fatty acids, allowing it to pass through the intestine undigested.
Problem discovered with Olestra
Frito-Lay Study: Olestra causes “anal oil leakage”
- Frito-Lay marketed olestra-containing chips (“max” potato chips and corn chips)
- Frito-Lay report stated that anal oil leakage symptoms were observed in a study but despite this concluded that olestra-containing snacks “should have a high potential for acceptance in the marketplace”
- In a memo, the company made a risk management plan to manage public perception of olestra-related digestion issues and handle any other issues
Olestra banned in UK and Canada because it restricts body’s ability to absorb essential vitamins - also, associated with cramps, bloating, gas, loose bowels
Omega-3 and Omega-6 Fatty Acids
- PUFAs
- number denotes the location of the final C=C
Omega-3 fatty acids (UFAs):
- essential (e.g. linolenic acid, eicosapentanoic acid (EPA), docosahexanoic acid (DHA), docosapentanoic acid (DPA))
- common components in marine and plant oils
- fish (salmon, tuna, halibut), nuts
- REDUCES inflammation (counters inflammatory and disease states)
- EPA responsible for production of prostaglandin 3
- C=C is closer to the end of the chain
Omega-6 fatty acids (UFAs):
- essential (e.g. linoleic acid, eicosadienoic acid)
- poultry, eggs, wheat, vegetable oil
- precursor to Prostaglandin 2, a ‘pro-inflammatory’
- excessive amounts of AA in our Omega-6 rich western diets MAY contribute to a chronic inflammatory state -> link to degenerative diseases (CVD, asthma, lupus, MS, arthritis??)
- INDUCES inflammation
- Balancing omega-6 to omega-3 ratio: thought to promote a homeostatic, non-inflammatory state in the body (higher ratios thought to promote an inflammatory state)
Ideal Western Diet: strive for omega6/omega3 of 4:1 (most optimal diet is 1:1)
- modern Western diets typically have ratios of 10:1 (junk food junkies as high as 50:1)
Inuit Diet and Health
- They eat walrus meat
- Walrus meat provides a well-balanced source of nutrients, especially young walruses
- Igunak (anaerobically fermented and aged meat) remains a traditional Inuit delicacy
- The skin is an excellent source of protein
- Walrus blubber (fat layer) EATEN RAW, aged or or boiled, is rich in Vitamin A - also rich in omega-3 fatty acids, which help prevent heart disease and cancer
- typical ratio of omega 6/omega 3 is 4:1 (MAX) even close to 1:1 or lower
Diet:
- man-made vegetable oil diets (margarine and other hydrogenated oils) are high in Omega-6 fatty acids. In contrast, Inuits consume large amounts of seal meat –> significant amounts of EPA, DHA, DPA (DPA is NOT readily found in fish oils - important factor for preventing CVD)
- EPA is a huge factor in fighting inflammation while DHA is an essential molecule for brain, nerve and eye tissues, and is a powerful factor for normalizing blood and tissue triglycerides
