NTR 326 Exam 4 Review PDF

Summary

This document contains lecture notes on protein synthesis and dietary considerations, particularly high-protein, high-fat diets. It discusses how protein type impacts body utilization and reviews the benefits and drawbacks of different dietary approaches. The document is likely part of a larger biology or nutrition course.

Full Transcript

Lecture 18 – 21 Protein Synthesis (Anabolic) Anabolic processes, including protein synthesis, increase in tissues following ingestion of food – because the ingested aa are the building blocks for making: ✓ Proteins ✓ Carbohydrates ✓ Hormones ✓ Etc. However, the kind of protein co...

Lecture 18 – 21 Protein Synthesis (Anabolic) Anabolic processes, including protein synthesis, increase in tissues following ingestion of food – because the ingested aa are the building blocks for making: ✓ Proteins ✓ Carbohydrates ✓ Hormones ✓ Etc. However, the kind of protein consumed can influence how our bodies utilize the AA from ‘fast proteins’ (eg. whey and soy protein, amino acid mixtures and partially hydrolyzed proteins all seem to be utilized differently from proteins derived from ‘slow proteins’ like casein Fast protein digestion causes blood plasma levels of aa to rise quickly and higher (hyper-amino-acidemia) but also to fall faster than equal amounts of slow protein ingestion fast protein ingestion also promotes transiently higher aa deamination; + therefore higher urea production in the liver Interestingly, when the fact that whey protein was discovered to peak plasma aa levels faster and higher, the Nutraceutical companies began selling whey protein – a byproduct of cheese production – at a very high cost & profit Whey is usually only fit for use as animal feed Marketed as an anabolic protein to build muscle mass However, fast proteins tend to be utilized in the intestines and abdominal area more than in the muscles And these marketers failed to recognize that casein prevents protein degradation better than whey So even in the case of bodybuilders, there is little advantage of either fast or slow forms of protein ingestion on overall protein creation: they both provide sufficient proteins for growth The type of protein consumed does influence how the body utilizes it, but overall either satisfies basic requirements to maintain homeostasis – or not Fast versus slow protein consumption may have short term effects on how aa are utilized, but little long term effects Hormones strongly regulate protein utilization short term: ▪ During an overnight fast, protein synthesis slows (because it requires energy) and protein catabolism increases ▪ Protein degradation is stimulated by 2 major hormones: Glucagon : stimulates the liver to synthesize enzymes involved in gluconeogenesis and ureagenesis Cortisol : promotes muscles to undergo protein catabolism and stimulates the liver to synthesize enzymes involved in gluconeogenesis and ureagenesis In contrast, 2 hormones involved in anabolic processes include insulin and growth hormone Insulin secretion rises with both: increased blood glucose AND in response to an increase in certain aa Insulin binds to the insulin receptor or to the IGF-1 receptor and initiates a signal transduction cascade that stimulates protein uptake & synthesis and inhibits protein degradation ✓ Effect enhanced by consumption of both carbs and aa High-protein, high-fat diet (Adkin’s): Nutritionists recommend the following proportions… ✓ 55-60% from carbs, 10-15% from protein, and no more than 30% from fat For the average American, adherence to these proportions would require an increase in carb consumption and a decrease in both protein and fat Despite this, fad (low carb) diets are popular. The premise is: Because the TCA cycle is the primary site of fat metabolism and because carbohydrates are normally required to replenish intermediates of TCA, then by limiting carbs, the consumed fat will not enter OXPHOS (which is very efficient at generating energy – ATP) Instead, protein – which require large amounts of energy to be digested and absorbed and metabolized (urea cycle); coupled with the inefficient conversion of fat into ketone bodies – which would be excreted in the urine & result in weight loss. Problems with the premise: Low carb diets appear to work at first because carbohydrates are suspended in water - remember: trehalose – 1,1 glycosidic linkages – retains water for anhydrobiosis Reducing carb intake would initially result in water loss (therefore weight loss) ✓ 3 grams of water hydration lost for every gram of glycogen Additional water loss accompanies ketone body excretion and the excretion of urea generated by the metabolism of excess protein Increased protein consumption requires energy for digestion / absorption and metabolism BUT : Long term results are disappointing and dangerous because: 1) Ketone body excretion by the human body does not exceed 20 grams/day 2) Amino acids can replenish TCA cycle intermediates – making the reduced carb regimen irrelevant 3) The fare in this diet is monotonous and expensive – so difficult to maintain 4) Over time, high fat diets contribute to coronary artery disease, and atherosclerosis 5) Chronic increases in production of ketone bodies (which happens in diabetes), damages the kidneys “Principles of Biochemistry with a Human Focus” Garret & Grisham; Chapt. 14 p.452 Amino Acids and Polypeptides: Many proteins contain only amino acids – and no other chemical groups and are called simple proteins (eg. Actin) The vast majority of proteins contain various chemical constituents as an integral part of their structure and function – are called conjugated proteins o if the non-protein group is critical for proper protein function, that group is called a prosthetic group Conjugated proteins are classified according to the chemical nature of their prosthetic group: 1) Glycoproteins – proteins that contain carbohydrates – proteoglycans make up the brush border in the GI tract 2) Lipoproteins – proteins conjugated to lipids – LDLs and HDLs transport cholesterol in the blood plasma & are used as a clinical index of cardiovascular health 3) Nucleoproteins – protein-nucleic acid complexes that facilitate storage and transmission of genetic information 4) Phosphoproteins – the presence or absence of Pi at critical Ser or Thr residues regulates enzyme kinetics Casein – the major protein in milk is rich in phosphates and brings essential phosphorus to the growing infant 5) Metalloproteins – proteins that either store metal atoms (ferritin); or enzymes in which the metal ions participate in catalyzing a reaction – discuss in depth 6) Hemoproteins – a subclass of metalloproteins because their prosthetic group is a heme (Fe+2) – but there are so many prominent heme-containing proteins they are considered a distinct class 7) Flavoproteins – flavin is an essential substance for the activity of a number of oxidoreductases (eg. FAD) Enzyme Specificity: Cells are teaming with scores of thousands of protein intermediates. Specific enzymes (pyruvate kinase) specifically recognize phosphoenolpyruvate and transfers a Pi to ADP and yields pyruvate. o How do enzymes ignore many similar substrates and bind only the ‘correct’ ones? Shape – determined by protein folding Size – determined by the overall sequence of the DNA/AA Chemistry – determined by the category of AA side groups at and neighboring the catalytic site o Enzymes are mostly protein (some contain RNA too) – so the AA sequence of the substrate AND the enzyme influence specificity Enzyme regulation: Once an enzyme binds to its correct substrate, the speed of the reaction is regulated: o Allosteric–effector molecule binds to the allosteric site o Covalent regulation – Pi is covalently attached as a prosthetic group to activate or inhibit an enzyme o Coenzymes – nonprotein component of an enzyme may be metal ions or organic molecules o Serve as intermediate carriers of functional groups in the conversion of substrates to products Many coenzymes are vitamins (B12) When a coenzyme functions as a prosthetic group and is required for catalytic activity, then the coenzyme + enzyme together are called holoenzymes When the coenzyme is missing from the holoenzyme, the protein without the prosthetic group is called an apoenzyme Functional Roles of proteins and nitrogen-containing nonprotein compounds: Proteins make up over ½ the solid content of cells and have a diverse number of roles: ❑ Catalysts : change the rate of reactions occurring in the body or promote chemical changes that could not otherwise occur (eg. kinases, dehydrogenases, decarboxylases – all required for life) ❑ Messengers : Some proteins are hormones. Hormones act as chemical messengers in the body (eg. proinsulin is a protein hormone made by the pancreas) ❑ Structural proteins : collagen, elastin and keratin are found in the teeth, bone, skin, blood vessels, hair and nails ❑ Buffers : hemoglobin helps regulate acid-base balance in the blood by accepting or donating a H+ to help maintain the blood pH between 7.35 to 7.45 ❑ Fluid balancers : In addition to acid-base balance, proteins influence fluid balance by attracting and retaining water inside cells or blood diminished blood/plasma concentrations of proteins – (eg. albumin) results in a decrease in plasma osmotic pressure ❑ Immunoprotectors : 5 major classes of immunoproteins include: IgG, IgA, IgM, IgE, and IgD - all produced by plasma cells derived from B- lymphocytes they bind to antigens to inactivate them and create immunoprotein-antigen complexes that attract T-helper cells and macrophages to destroy them NADPH donates electrons to NADPH oxidase in the cell membrane of macrophages to produce ROS ❑ Acute phase responders : in response to sudden (acute) illness, the liver releases proteins in response to infection (sepsis), injury or inflammation: C-reactive protein, fibronectin, haptoglobin, serum amyloid A and metallothionein Collectively, these proteins protect the body, promote wound healing, chleate iron from the blood – so bacteria can’t use it -, and stimulate the immune system ❑ Other roles – varied – including acting as a source of nitrogen for the body Nitrogen-containing Nonprotein Compounds: Amino Acids are used to synthesize nitrogen-containing compounds that are not proteins, but which still play important roles in the body: Important Functions of Nitrogen Containing Nonproteins Histamine (Histidine) drives allergic reactions Purines, Pyrimidines (Gln, Asp) DNA, RNA synthesis Glutathione (Cys, Glu, Gly) a potent antioxidant Thyroid hormones, melanin (Tyr) metabolic regulation Tyrosine (Phe) biosynthesis of Phe Creatine (Arg, Gly) fatty acid oxidation Dopamine, Norepinephrine, metabolic regulation Epinephrine (Tyr) Ethanolamine, Choline (Ser) phospholipid polar head groups smooth muscle relaxer, blood pressure regulation, Nitric Oxide (Arg) immune function Nitrogen-containing Nonprotein Compounds: Glutathione : synthesized from cysteine, glycine and glutamate – linked by gamma-linkages – so not technically a protein although it contains amino acids Contains a sulfhydryl group (-SH) group in its reduced form Functionally, glutathione serves as an antioxidant in the cytosol of most cells by scavenging free radicals from hydrogen peroxide (H2O2) and lipid peroxyls (LOOHs) Glutathione also transports amino acids as part of the γ-glutamyl cycle It participates in synthesis of leukotrienes – which mediate inflammation Glutathione is sensitive to protein consumption – when systemic, hepatic or intestinal levels of protein intake decrease to very low levels, glutathione levels also decline Nitrogen-containing Nonprotein Compounds: Carnitine : another nitrogen containing compound made from a methylated lysine that further becomes hydroxylated to generate carnitine Iron, B6, vitamin C and niacin all participate in generating carnitine in the liver and kidneys Also found in meats in free forms or bound to short-chain fatty acid esters (acylcarnitine) Absorbed in the proximal (jejunum) intestines by passive diffusion or by sodium-dependant active transport 2g of carnitine is absorbed daily and stored primarily in the skeletal muscles Needed by most body tissues for transport of fatty acids across the inner mitochondrial membrane for lipid β-oxidation, Also needed for ketone catabolism for energy. Carnitine deficiency – although rare – impairs energy metabolism Often marketed to help burn fat or enhance energy – both claims are false Nitrogen-containing Nonprotein Compounds: Creatine : key component of creatine phosphate, available from the diet (meat or fish) OR is synthesized in the kidneys, then released and stored in the muscles (95%) o Creatine phosphate functions as an energy reserve (backup or storehouse for high energy phosphate), and can quickly replenishes ATP in a muscle that is rapidly contracting ▪ During peak exercise, ATP can supply a muscle with energy for only a fraction of a second. Then creatine phosphate can transfer a Pi to ADP, providing energy for muscular activity ▪ The transfer of Pi from creatine phosphate to ADP is catalyzed by creatine phosphokinase. ▪ Once the creatine phosphate stores are consumed (creatinine is excreted in the urine), muscle tissue then hydrolyzes glycogen into glucose to replenish stores of ATP ▪ It is a popular supplement and has been shown to increase muscle creatine levels by ~20-50% and enhance short-duration, high-intensity exercise (sprints / weight lifting) with typical load doses of 5g 4x/day for 4-6 days followed by intake at 2-5g daily. No known side effects Nitrogen-containing Nonprotein Compounds: Carnosine : made from histidine and is found in the skeletal muscle, cardiac muscle, brain, kidneys, and stomach Available in foods – primarily in meats It acts as a buffer and an antioxidant It may also help reduce calcium needs for muscle contractility Supplementation does increase muscle carnosine concentration however the benefits and side effects are relatively unknown Choline – made from methylation of serine using S-adenosyl mehtionine (SAM) pathway Found in foods rich in lecithin (eggs, liver and other organ meats) and legumes (soybeans and peanuts) Choline has several functions: Methyl donor Promotes the formation of platelet aggregating factor Enhances secretion of very low-density lipoproteins (VLDLs) from the liver Needed to synthesize the neurotransmitter acetylcholine Deficiency of choline in the diet can cause fatty liver and hepatic necrosis Lecture 22 Digestion and Absorption Digestion of triglycerides occurs in the lumen of the small intestines ✓ But process begins in the mouth & stomach– secretion of lingual & gastric lipase ; produced by the serous gland and chief cells, respectively Gastric lipase is very stable, even in low pH and without bile salts Important for milk digestion in infants Pancreas is still developing Both lingual and gastric lipase work preferentially on medium and short chain fatty acids, hydrolyzing the c-3 position, thereby releasing a FFA & a 1,2-DAG The partially digested lipids exit the stomach in the chyme In the duodenum, hormones stimulate the pancreas and gallbladder to release digestive enzymes and bicarbonate and bile Pancreatic lipase preferentially digests the fatty acid attached to c-1 ❖ Premature infants are fed high-energy formulas containing TAGs with medium and short chain fatty acids to aid digestion and absorption Lipids are insoluble in water Oils are liquid at room temperature (PUFA) Fats are solid at room temperature (sat. fat) Diet is 96T TG Triglyceride digestion by lipases: 1 2 3 Together the action of lingual, gastric and pancreatic lipase + bile salts results in an emulsion of TAGs + DAGs + MAGs + FFAs + cholesterol in the jejunum The majority of lipid absorption occurs in the jejunum The majority of digestion ALSO occurs in the distal duodenum and jejunum, primarily by the action of bile salts and pancreatic lipase Pancreatic lipase activation is complex: ✓ Requires the participation of the protein colipase, calcium ions and bile salts ✓ Like the intestinal peptidases, procolipase is activated by trypsin into colipase ✓ Remember that enteropeptidase activates trypsinogen into trypsin Colipase has over 100 aa residues that are hydrophobic that bind to lipids and then is thought to anchor to lipase, allowing hydrolysis Bile salts facilitate the action of colipase and lipase and are secreted into the duodenum in response to the presence of fat in the chyme ✓ Increases the surface to volume ratio of fat globules The small intestine can digest and absorb a large quantity of TAGs (660 grams/day of TAGs (at 95% efficiency)! With MOST TAG digestion occurring in the upper segment of the jejunum And most absorption occurring there too Inhibitors of gastric & pancreatic lipase have been developed to reduce absorption of dietary TAGs (orlistat): 1. Xenical – prescription only; inhibits 30% absorption (200 grams fat/day) 2. Alli – over the counter Absorption of emulsion containing TAGs, DAGs, MAGs, FFA, glycerol and cholesterol: Micelle particles are sufficiently small and water soluble & can penetrate the enterocytes within the small intestine The mechanism for moving fatty acids across the luminal membrane is not fully understood: 2 mechanisms have been proposed: 1. lipid diffusion across the membrane 2. a protein-dependent model in which fatty acid transport protein (FATP) allows passage of lipids into the enterocytes FATP 1-4 proteins have been characterized Neither mechanisms (diffusion or FATP transport) require energy for absorption Again the majority of lipid digestion and absorption occurs in the distal duodenum and jejunum But the bile salts are not absorbed until they arrive at the illeal segment of the small intestine ✓ Returned to the liver via the portal vein to be resecreted in the bile (circuit called the enterohepatic circulation of bile salts) Stimulation by cholecystokinin (CCK) promotes release of bile from the gallbladder Bile salts emulsify (breakdown large fat globules into smaller, uniform particles) Q. Why are emulsifying agents so effective in digesting fats? A. Emulsifying effectiveness is due to the amphipathic properties of bile salts: Possess BOTH hydrophilic and hydrophobic ‘ends’ Amphipathic molecules tend to arrange themselves on the surface of small fat particles with their hydrophobic ends turned inward and their hydrophilic ends turned outward to break up fat globules into smaller droplets with greater surface area, allowing pancreatic lipase to function more efficiently C #3 C #1 Enterocyte Cholesterol: 80% of our cholesterol is synthesized in our liver, the other 20% comes from the animal-based foods we consume Triglyceride and Cholesterol Digestion: In the small intestine, the enzyme cholesterol esterase hydrolyzes the esterfied cholesterol from the food in our diet Any fatty acids attached to the cholesterol are cleaved off by the enzyme phospholipase A2 The free fatty acids and cholesterol then combine with bile salts to form micelles Micelles transport digested lipid components enterocytes The SER of the enterocytes modify and package lipid components into chylomicrons for transport to the liver Synthesis of Bile salts from cholesterol: Cholesterol is oxidized to form cholic acid Then conjugated bile salts are formed: Cholesterol absorption: Average American males consumes over 362 mg/day Average American females consume over 230 mg/day Over 1 gram (1,000 mg) is excreted by the liver into the intestines, and only about ½ of that is reabsorbed Cholesterol is absorbed from the micelle in the jejunum along with the TAGs, DAGs, MAGs and FFAs Cholesterol is absorbed by a facilitated transporter called the ‘Nieman-Pick C1 (NPC1L1) (no energy required) Question: Why would cholesterol absorption inhibitors be more beneficial to lowering cholesterol than simply eliminating animal products from the diet? After the cholesterol is absorbed into the enterocyte and transported to the ER, it is esterfied by 2 enzymes found on the ER membrane called: 1. cholesterol acyltransferase 1 (ACAT1) 2. cholesterol acyltransferase 2 (ACAT2) These enzymes are highly specific for cholesterol and do not recognize plant sterols (good thing) Approximately 70-80% of cholesterol entering the lymphatic system is esterfied Theses esterfied cholesterol molecules are incorporated into chylomicrons OR very-low-density lipoproteins (VLDLs) with other lipid components: FFAs, TAGS, DAGs, MAGs, fat-soluble vitamins Chylomicrons and VLDLs undergo exocytosis from the enterocyte into the lymphatics – to ultimately reach the liver as chylomicron remnants Chylomicrons are large TAG-rich spherical particles that contain all the digested lipids TAGS-FFAs etc. + fat-soluble vits. surrounded by a phospholipid bilayer Digested triglycerides are assembled into chylomicrons in the enterocytes and transported to the liver The protein added to the surface of the chylomicron is very hydrophobic and stabilizes the chylomicron as it travels in the blood ✓ called apolipoprotein B-48 (apo-48) ✓ other apolipoproteins are also incorporated: apoA-1, apoA-4 and apoC Fatty acid binding protein (FABP) is also required for chylomicron formation ✓ FABP synthesizes TAGs from DAGs and MAGs Once the prechylomicron vessicle is formed, it pinches off the enterocyte’s ER and travels and fuses with the Golgi → carbohydrates are attached to the protein coat (why?) and the completed particles are transported to the cell membrane and excreted by exocytosis Enterocytes also make small amounts of VLDLs (liver is the major site of VLDL formation) Lecture 23 - 25 Lipids are distinct from carbohydrates and amino acids in that they are mostly hydrophobic and soluble in organic solvents (alcohol, ether, chloroform and acetone) Lipids have broad functions in cells including: Serves as dietary source of energy; 1 gram of fat yields 9 kCal vs 4 from carbs Structural component of cells (lipid bilayers) The fat content of a mammalian brain is ~60% Function together with proteins (lipoproteins) Function as fat-soluble vitamins Function as corticosteroid and sex hormones Participate in REDOX reactions (coenzyme Q in electron transport chain) Today we will focus on the structure and function of dietary lipids & introduce you to some of the biologically relevant metabolites and signaling molecules that they are converted into: Basic structure of lipids and their nomenclature Essential vs. nonessential Polyunsaturated fatty acids (PUFAs) How PUFAs are used as signaling molecules Or metabolized into eicosanoids Digestion and Absorption Structure and function of fatty acids: Fatty acids are the simplest lipids : composed of a straight hydrocarbon chain terminating with a carboxylic group (similar to the aa carboxylic group) They have a polar (hydrophilic) carboxyl end And they have a (CH3) nonpolar, hydrophobic end that is insoluble in water The length of the hydrocarbon chains in fatty acids range from 4 to about 24 carbon atoms The length of the fatty acid chain can be saturated (SFA), containing no C=C bonds Or monounsaturated fatty acids may contain one C=C bond Or polyunstaurated fatty acids may contain multiple C=C bonds (PUFA) Polyunsaturated Fatty Acid Nomenclature: There are 2 systems of notation developed to provide a shorthand way to describe the chemical structure of a fatty acid The delta (∆) system describes the chain length, and the number and position of any double bonds in the fatty acid chain (ex) Linoleic acid is 18:2∆9,12 This means the fatty acid chain is 18 carbons long, has 2 double bonds at carbons 9 & 12 9 1 12 ? Fatty Acid Nomenclature: The more common system determines the location of the double bonds beginning at the methyl (or omega) end of the carbon chain Omega (ω – now substituted with the letter n describes the position of the first double bond) (ex) Linoleic acid is 18:2 ω-6 fatty acid or 18:2 n-6 This system describes linoleic acid as an 18-carbon chain fatty acid with 2 double bonds with the a double bond at the 6th carbon from the end Even with less description, you know all the locations of the double bonds because you know the total number of double bond AND there are always 3 carbons separating double bonds 6 Fig. 5-1, p. 132 Fatty Acids: Fat is necessary in the human diet (but the type of fat and amount should be consumed in moderation) Complete exclusion of fat from the diet can cause a condition characterized by: Retarded growth Dermatitis Kidney lesions Death Although our metabolic processes can synthesize some fatty acids from the hydrocarbon skeletons of amino acids or of the hydrocarbon moieties from carbohydrates (pyruvate) including: n-7 n-9 saturated fatty acids The essential fatty acids (which we can’t make) are very important components of the brain and cellular bilayers & are used to make signaling molecules Non-essential fatty acids: can be synthesized in the body from amino acids and carbohydrates Essential Fatty Acids: (can not be made in the body): ▪ These essential fatty acids are very important because they are used as the building materials needed to make many of the cell’s signaling molecules that control: Inflammation Immune response and cellular health / aging Oxidative stress Cell to cell communication The integrity of the lipid bilayer Cox-1/2 PUFAs of nutritional interest may contain as many as 6 C=C double strand bonds Remember: a double bond allows for either a cis or trans geometric isomerism that affects the molecular ‘shape’ and function of the molecule The cis-isomer form results in a folding back and U-shaped orientation The trans-isomer form results in an extended linear shape, similar to saturated fatty acids The more cis-form C=C double bonds, the more pronounced the bending effect The degree of bending plays an important role in the structure and function of cell membranes The two essential fatty acids (both PUFAs) are: ✓ linoleic acid (n-6) ✓ α-linolenic acid (n-3) These two fatty acids are essential because humans lack the enzymes called ∆12 and ∆15 desaturases which add double bonds at n-6 and n-3 carbons N-3 DHA (n-3) AA (n-6) 1 N-6 DHA = 22:6 While both the n-6 and n-3 fatty acids are essential or conditionally essential, we require both varieties for normal homeostasis, they have separate and complimentary functions in cells n-6 fatty acids are converted into eicosanoids that promote inflammation n-3 fatty acids are converted into eicosaniods that inhibit inflammation In the context of human conditions, where inflammation is thought to be causing a disorder: ✓ allergies ✓ psoriasis ✓ arthritis ✓ autoimmune diseases AA ✓ etc. We tend to blame the existence of n-6 PUFAs (which are converted into inflammatory signaling molecules) for the disease – we frequently call these the ‘bad PUFA fats’ Perhaps consumption of foods that contain too many n-6 do adversely affect health, but these fatty acids are also critical for important biological responses: ✓ immune defense ✓ coagulation ✓ cell differentiation ❑ Polyunsaturated fatty acids have distinct chemistries and biological effects n-6 fatty acids (arachidonic) are metabolized by cells into inflammatory n-6 eicosanoids: n-6 prostaglandins : Series E2 prostaglandins n-6 leukotrienes n-3 fatty acids (DHA, EPA) tend to be metabolized by cells into anti-inflammatory n-3 eicosanoids: n-3 prostaglandins : series D/J prostaglandins n-3 leukotrienes But just because PUFAs are referred to as ‘good fats’, too much of a good thing can be very bad – in elderly and during cancer treatment PUFAs are used to make eicosanoids: signaling molecules made by oxidation of 20-carbon essential fatty acids & control many bodily systems – including inflammation and immune response Classes of eicosanoids: Prostaglandins: any of a group of naturally occurring, chemically related fatty acids that stimulate contractility of the uterine and other smooth muscle and have the ability to lower blood pressure, regulate acid secretion of the stomach, regulate body temperature and platelet aggregation, and control inflammation and vascular permeability; they also affect the action of certain hormones. Nine primary types are labeled A through I, the degree of saturation of the side chain of each being designated by subscripts 1, 2, and 3. The types of prostaglandins are abbreviated PGE2, PGF2α, and so on Leukotrienes: Biologically active molecules metabolized from AA in mast cells and leukocytes that induce inflammation LTA4, LTB4, LTC4, LTD4, LTE4 Thromboxanes: Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. It induces platelet aggregation and vascular constriction Eicosanoids are derived from essential or conditionally essential fatty acids: Biologically active molecules metabolized from AA in mast cells and leukocytes that induce inflammation LTA4, LTB4, LTC4, LTD4, LTE4 Arachidonic Acid is stored in the lipid bilayer IL-6r Metabolic Intermediates of AA NSAIDS (COX) COX-1 is a housekeeping gene COX-2 is inducible (activated in response to stress / cytokines) NSAIDs Block COX-1/2 Bad Fats: Trans fatty acids Trace-levels of trans fats can be acquired from meat and dairy sources (1-3 % of total fat) The majority of trans fatty acids are derived from partially hydrogenated fats and oils ✓ partial hydrogenation is a common process in making margarine and frying oils ✓ Purpose: to solidify vegetable oils at room temp ? Why did the food industry take relatively healthy vegetable fats (compared to animal fat) and partially hydrogenate it? Vegetable oils are cheaper than animal fats But they oxidize (go rancid) quickly The process increases the smoke point of vegetable oils & increases the melting point And it enhances the texture and flavor of foods And makes the food seem less greasy Health implications of trans fats: The National Academy of Sciences (NAS) recommends that because trans fats are not essential, and have no known beneficial effect on human health, that we should limit severely intake Also, while saturated fat and trans fat both increase LDL cholesterol, trans fats also lower HDL cholesterol; therefore increasing the risk of coronary heart disease (CHD) The association between trans fats in the diet and CHD are highlighted by the Nurses’ Health Study NHS are the largest and longest running investigations of factors that influence women’s health Began at Harvard (with the help of Dr. Willet) in 1976 and is currently ongoing. NHS3 (3rd generation) is currently recruiting nurses Nurses volunteer info. about themselves and are tracked until death Birth weight, Age of menarche, smoking, drinking, lifestyle, age of menopause, etc………….. Trans fats: ▪ Occur naturally at low levels in foods (vaccenic acid found in beef and dairy) No consensus on health implications of natural versus processed trans fats therefore limit to only trace amounts ▪ Encountered at very high levels in processed polyunsaturated fats Coronary Heart Disease (100,000 deaths/yr in US): Raises triglyceride levels Similar to saturated fats, trans fats raise low density lipoprotein levels (LDL) o LDLs transport cholesterol from the liver to the circulatory system (called hyperlipoproteinemia) contributes to atherosclerosis and ischemia Unlike saturated fatty acids, trans fats lower high density lipoproteins (HDL) ; which transport cholesterol to the liver for formation of bile Trans fats increased C-reactive protein – major biomarker for inflammation ▪ Trans fats also contribute to diabetes, cancer, obesity and liver dysfunction Interferes with a liver enzyme – n-6 desaturase – converts essential fatty acids to arachidonic (omega-6) fatty acid + prostaglandins Higher levels of C-reactive proteins – strong biomarker of inflammation Human lipase enzyme only works on the cis conformation resulting in accumulation of trans fats – contributes to obesity Non-human primate studies suggest that non-human primates maintained on a high trans fat diet gained 7% body weight/yr compared to 1.8% for animals maintained on unsaturated fat diets Fatty Acids are converted in the body to many classes of lipids: 1. Triacylglycerols – major storage form of dietary fat in adipocytes 2. Sterols (steroids) – lipids characterized by the 4-ring core structure [cholesterol] : May or may not be associated with a fatty acid 3. Phospholipids – major component of the lipid bilayer ✓ Glycerophosphates ✓ Sphingolipids 4. Glycolipids – contain a carbohydrate attached to the lipid structure and, like phospholipids, are not used as energy, but as structural components of cells particularly in the white matter of the central and peripheral nervous system 5. Eicosanoids – metabolites of PUFAs that act as signaling ligands for a variety of receptors 6. Other – waxes 1. Triacylglycerols : most stored body fat is in the form of triacylglycerols (TAG) or triglycerides ▪ Plants and animals synthesize (TAGs) ▪ Highly concentrated form of energy ▪ Account for 95% of dietary fat ▪ In humans, is stored primarily in the liver, adipocytes and intestines ▪ Consists of 3 fatty acid tails attached (by the carboxyl terminus) to a single glycerol (carbohydrate) Most cells store TAGs as lipid droplets or ‘adiposomes’ within the cytosol of the cell as an energy reserve when the cell doesn’t need ATP Excess glucose in the cell is first Pi’d by hexokinase to prevent it from diffusing out of the cell through the GLUT transporters Then after aldolase cleaves the 6-carbon molecule into 2x3-carbon molecules, (glyceraldehyde 3-phosphate & dihydroxyacetone – which is interconverted back into G3P), then this intermediate shunts off from glycolysis and becomes substrate for an enzyme called glyceraldehyde phosphate acetyltransferase glyceraldehyde phosphate acetyltransferase links multiple 3-carbon G3Ps into fatty acids Glucose GPAT GPD TAGs Glyceraldehyde 3-phosphate pyruvate Fat storage Krebs TAG synthesis pathways: The glycerol-3-phosphate pathway (GPAT) synthesizes TAGs predominantly in the liver and adipocytes Krebs cycle Instead of continuing in glycolysis to make pyruvate and ultimately ATP, it diverts to a lipid synthesis pathway Triacylglycerol Structure: 1. Glycerol 2. 3 fatty acid tails Plasmolagen Structure: A Unique Phospholipid Plasmolagens have a vinyl ether linked fatty acid in the sn-1 position. TAG Structure : the fatty acid tails on this molecule may all be saturated, monounsaturated or polyunsaturated OR any combination of the three Glycerol is the water-soluble backbone of all triglycerides The FDA categorizes glycerol as a carbohydrate – commonly used as a sweetener and a thickening agent in liqueurs It can reenter glycolysis pathway if cells contain glucokinase which phosphorylates it back into G3P So when we hydrolized fatty acids (triglycerides) for fuel, we also release a small amount of carbohydrate Triacylglycerols can exist as a solid or liquid, depending on which fatty acids are attached to the glycerol backbone ✓ TAGs that contain a high proportion of short chain or unsaturated fatty acids tend to remain liquid at room temp. ✓ TAGs made up of longer chain lengths or saturated fatty acids have a higher melting point and therefore exist as solids at rt. When a fatty acid is needed for energy, fatty acids are released from the glycerol backbone as free fatty acids (FFA) by the activity of lipases. The FFA are then transported by albumin in the blood to various tissues for oxidation Unlike carbohydrates, proteins (aa) and DNA, which are digested and absorbed as monomers or dimers, the type of fatty acids we consume DO become absorbed and incorporated in our tissues and cells Example: ▪ Olive oil is composed mostly of triacylglycerols that contain oleic fatty acids (80%) conjugated to glycerol ▪ Also contains linoleic (20%) and palmitic/stearic etc. O O O x3 O O S O O P ▪ Also contains some FFA, DAGs, glycerol, pigments, sterols and microscopic bits of olives Since TAGs are easily stored as fat… while DAGs are intermediates that can either: Absorb a FFA to yield a TAG – so excess carbs or aa are formed into FFA and absorbed into the DAG OR is quickly catabolized for energy So a patented, chemical process was developed where the DAG : TAG ratio was increased Enova brand oil developed and sold in the USA in 2009 – 2011 Contains 80% DAG Was labeled ‘Generally Recognized as Safe’ (GRAS) by the FDA Was found not to be stored as fat But was recently voluntarily pulled from shelves because it contains potentially harmful glycidyl esters (epoxy resins) glycidyl ester of stearic acid 2. Sterols (steroids) – lipids characterized by the 4-ring core structure [cholesterol] This class of lipid contains a or steroid core (solid pink) Cholesterol is the most common form of sterols in animals and is the generic precursor for making other steroids Cholesterol can exist in the free form or with the hydroxyl group attached to a fatty acid: Free form of cholesterol Cholesterol attached to FA Plants do not make cholesterol, but plants make other sterols – some of which interfere with cholesterol absorption in humans Most human enzyme systems are specific for cholesterol and do not react with plant sterols The numbering system for sterols is: Very hydrophobic – can diffuse through cell membranes About ½ of cholesterol is consumed from the diet Meats Egg yolk Dairy Q. if we don’t use plant sterols as a precursor to make cholesterol, then what is the source? A. We make cholesterol from acetyl-CoA = A series of enzymes (Mevalonate pathway) takes acetyl-CoA away from TCA and synthesizes cholesterol in the liver – because the liver has this enzyme Cholesterol levels increase when we consume animal products because: We make our own cholesterol in the liver In addition, we consume the cholesterol that our animal-based food made in their livers But cholesterol is vital for normal cell function: Used to make steroids – sex steroids (androgens: estrogen, testosterone) Corticosteroids – glucocorticoids (made by adrenal glands – regulate bp) Bile acids – for emulsification of fats in the digestive tract Precursor for production of vitamin D These steroids differ from one another: ✓ In the arrangement of double bonds in the ring system ✓ The presence of hydroxyl or carbonyl groups ✓ The chemistry of the side chain located at C-17 ✓ A host of enzymes make structural modifications to the core ring to make various sterols Liver cholesterol Synthesis: HMG-CoA reductase is the rate-limiting step in the Mevalonate pathway, which synthesizes cholesterol from acetyl-CoA when citrate is transported out of the mitochondria and into the cytosol where it dissociates into oxaloacetate and acetyl-CoA Fatty acids are NOT used to synthesize Cholesterol! Oxidized LDL is Key Maxwell, SRJ. 2000. Basic Card. Res. 95(1):I/65. ✓ 80% of our cholesterol is synthesized in our liver, the other 20% comes from the animal-based foods we consume Dietary Cholesterol Digestion: In the small intestine, the enzyme cholesterol esterase hydrolyzes the esterfied cholesterol from the food in our diet Any fatty acids attached to the cholesterol are cleaved off by the enzyme cholesterol esterase The free fatty acids and cholesterol then combine with bile salts to form micelles Micelles transport digested lipid components enterocytes Enterocytes modify and package lipid components into chylomicrons for transport to the liver EXAM 4 REVIEW Protein Synthesis (Anabolic) Interestingly, when the fact that whey protein was discovered to peak plasma aa levels faster and higher, the Nutraceutical companies began selling whey protein – a byproduct of cheese production – at very high cost & profit Whey is usually only fit for use as animal feed Marketed as an anabolic protein to build muscle mass BUT fast proteins tend to be utilized in the intestines and abdominal area more than in the muscles AND these marketers failed to recognize that casein prevents protein degradation better than whey So even in the case of body builders, there is little advantage of either fast or slow forms of protein ingestion on overall protein creation: they both provide sufficient proteins for growth So the type of protein consumed does influence how the body utilizes it, but overall either satisfies basic requirements to maintain homeostasis – or not High-protein, high-fat diet (Adkin’s): Nutritionists recommend the following proportions of carb : protein : fat ✓ 55-60% from carbs : 10-15% from protein and no more than 30% from fat For the average American, adherence to these proportions would require an increase in carb consumption, and a decrease in both protein and fat Despite this, fad (low carb) diets are popular The premise is: ✓ Because the TCA cycle is the primary site of fat metabolism and because carbohydrates are normally required to replenish intermediates of TCA, then by limiting carbs, the consumed fat will not enter OXPHOS (which is very efficient at generating energy – ATP) ✓ Instead, protein – which require large amounts of energy to be digested and absorbed and metabolized (urea cycle); coupled with the inefficient conversion of fat into ketone bodies – which would be excreted in the urine & result in weight loss Problems with the premise: Low carb diets appear to work at first because carbohydrates are suspended in water remember: trehalose – 1,1 glycosidic linkages – retains water for anhydrobiosis Reducing carb intake would initially result in water loss (therefore weight loss) 3 grams of water hydration lost for every gram of glycogen Additional water loss accompanies ketone body excretion and the excretion of urea generated by the metabolism of excess protein Increased protein consumption requires energy for digestion / absorption and metabolism BUT : Long term results are disappointing and dangerous because: 1. Ketone body excretion by the human body does not exceed 20 grams/day 2. Amino acids can replenish TCA cycle intermediates – making the reduced carb regimen irrelevant 3. The fare in this diet is monotonous and expensive – so difficult to maintain 4. Over time, high fat diets contribute to coronary artery disease, and atherosclerosis 5. Chronic increases in production of ketone bodies (which happens in diabetes), damages the kidneys “Principles of Biochemistry with a Human Focus” Garret & Grisham; Chapt. 14 p.452 Glycogen in Humans 70 kg person, healthy Skeletal muscle 400 grams = 1 lb + 3 lbs water Liver 120 grams = 0.25 lb + ¾ lb water Nitrogen-Containing Nonprotein Compounds: Amino Acids are used to synthesize nitrogen-containing compounds that are not proteins, but which still play important roles in the body: Important Functions of Nitrogen Containing Nonproteins Histamine (Histidine) – drives allergic reactions Purines, Pyrimidines (Gln, Asp) – DNA, RNA synthesis Gutathione (Cys, Glu, Gly) – potent antioxidant Thyroid hormones, melanin (Tyr) – metabolic regulation Tyrosine (Phe) – biosynthesis of Phe Creatine (Arg, Gly) – fatty acid oxidation Dopamine, Norepinephrine, Epinphrine (Tyr) – metabolic regulation Ethanolamine, Choline (Ser) – phospholipid polar head groups Nitric Oxide (Arg) – smooth muscle relaxer, blood pressure regulation, immune function Stimulation by cholecystokinin (CCK) promotes release of bile from the gallbladder Bile salts emulsify (breakdown large fat globules into smaller, uniform particles) Why are emulsifying agents so effective in digesting fats? Emulsifying effectiveness is due to the amphipathic properties of bile salts: Possess BOTH hydrophilic and hydrophobic ‘ends’ Amphipathic molecules tend to arrange themselves on the surface of small fat particles with their hydrophobic ends turned inward and their hydrophilic ends turned outward to break up fat globules into smaller droplets with greater surface area, allowing pancreatic lipase to function more efficiently C #3 C #1 Enterocyte Polyunsaturated Fatty Acid Nomenclature: There are 2 systems of notation developed to provide a shorthand way to describe the chemical structure of a fatty acid The delta (∆) system describes the chain length, and the number and position of any double bonds in the fatty acid chain (ex) Linoleic acid is 18:2∆9,12 This means the fatty acid chain is 18 carbons long, has 2 double bonds at carbons 9 & 12 9 1 12 ? Fatty Acid Nomenclature: The more common system determines the location of the double bonds beginning at the methyl (or omega) end of the carbon chain Omega (ω – now substituted with the letter n describes the position of the first double bond) (ex) Linoleic acid is 18:2 ω-6 fatty acid or 18:2 n-6 This system describes linoleic acid as an 18-carbon chain fatty acid with 2 double bonds with the a double bond at the 6th carbon from the end ✓ Even with less description, you know all the locations of the double bonds because you know the total number of double bonds AND there are always 3 carbons separating double bonds 6 Eicosanoids are derived from essential or conditionally essential fatty acids: Biologically active molecules metabolized from AA in mast cells and leukocytes that induce inflammation LTA4, LTB4, LTC4, LTD4, LTE4 Arachidonic Acid is stored in the lipid bilayer IL-6r NSAIDS (COX) COX-1 is a housekeeping gene COX-2 is inducible (activated in response to stress / cytokines) Fatty acids are NOT used to synthesize Cholesterol! Oxidized LDL is Key Maxwell, SRJ. 2000. Basic Card. Res. 95(1):I/65.

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