Biochemistry Study Guide Exam 2 PDF

Biochemistry Study Guide Exam 2 the structural features of fatty acids, triacylglycerols (TG), cholesterol, sphingolipids and glycerophospholipids The types of fatty acids are saturated (single bond only), mono-unsaturated (one double bond), and poly-unsaturated fatty acids (multiple double bonds)...

Biochemistry Study Guide Exam 2 the structural features of fatty acids, triacylglycerols (TG), cholesterol, sphingolipids and glycerophospholipids The types of fatty acids are saturated (single bond only), mono-unsaturated (one double bond), and poly-unsaturated fatty acids (multiple double bonds). The three essential fatty acids we should know are linoleic acid, a-linolenic acid, and arachidonic acid. Virtually all double bonds in naturally occurring polyunsaturated fatty acids are in cis configuration. Arachidonic acid is major precursor of eicosanoids/ Eicosanoids regulate inflammatory response, muscle contraction, blood pressure, and other things in the body. 3 cell membrane lipids to know are phosphoaglycerols, sphingolipids, and cholesterol. Glycerol is backbone of phosphoagylcerols. Phosphatidic acid and phosphatidylcholine aci are versions of phosphoaglycerol. Lecithin is another name for phosphatidylcholine. Phosphoaglycerols are key components of cell membranes. Play a pivotal role in signal transduction and metabolic pathways, help with cell membrane fluidity. Sphingolipids divided into sphingomyelin and sphingoglycolipid. All sphingolipids derived from ceramide. Sphingolipids are key components of cell membranes. Regulators in cell death/survival, toxin binding, and cell-cell recognition. Cholesterol is very non-polar and contains a tetracyclic ring. Humans do not have enzymes to degrade this ring structure. Free cholesterol can be converted to cholesterol esters. Phosphoaglycerols and sphingolipids can form lipid bilayers. Cholesterol, which is very non-polar can insert into the bilayers. Membrane proteins include integral proteins and peripheral proteins. Carbohydrate moieties residing in the extracellular side. the biological importance of essential fatty acids and the adverse effect of trans fatty acids Trans fatty acids found in food and are formed during hydrogenation, a process that adds hydrogen atoms to double bonds of unsaturated fatty acids. Turns cis bonds into trans bonds. Cis fatty acids make membrane packing loose while trans fatty acids make membrane packing tight. Trans fatty acids increase serum LDL cholesterol, triacyclglycerols, and platelet aggregation. They decrease HDL cholesterol. Fish oils are rich in W-3 polyunsaturated fatty acids which decrease cardiovascular mortality and are good for you. the ability and necessity of lipids to form bilayers, micelles, mixed micelles, and emulsion particles Digestion of dietary triaglycerides in the small intestine requires bile salts, pancreatic lipase, co-lipase, and bicarbonate. The anionic form (other deprotonated form or termed bile salt) exhibits detergent properties and helps contribute to digestion. Bile acids synthesized from cholesterol in the liver. Emulsion particles and mixed micelles to store non-polar lip particles on the interior region. Co-lipase helps attract and anchor the pancreatic lipase to the surface of the emulsion particles. how dietary TGs are digested and absorbed in the small intestine; the functional role of pancreatic lipase, co-lipase, bile salts and bicarbonate In small intestine, dietary triaglycerols hydrolyzed to 2-monoacylglycerol and fatty acids. Mixed micelles formed by FA, 2-MG, bile salts, and other lipid soluble materials are taken up by intestinal epithelial cells. Triaglycerols re-synthesized in intestinal epithelial cells combine with other lipid-soluble materials and apo-proteins to form chylomicrons. Lipid malabsorption: inability to digest triaglycerols due to pancreatic lipase or bile acid deficiencies. Can lead to lipid accumulation in feces called statorrhea. Leading to loss of important energy fuels, severe weight loss, and vitamin as well as essential fatty acid and caloric deficiencies. the reaction schemes (including cofactors, reactants, products, subcellular locations, major tissues, and key enzymes) associated with biosynthesis of fatty acids Both the malic enzyme pathway and the pentose phosphate pathway generates NADPH. Both NADPH and acetyl CoA are needed in order to synthesize long-chain fatty acids. The pentose phosphate pathway is active when fatty acid synthesis is active. The rate limiting step in fatty acid synthesis is the carboxylation of acetyl CoA to form Malonyl CoA by acetyl CoA carboxylase. Biotin serves as a carrier of activated CO2. Rate limiting enzyme for fatty acid synthesis = acetyl coa carboxylase. Fatty acids can be synthesized from dietary carbohydrates and proteins in many different tissues with the liver as the major site. the roles of malonyl CoA, biotin, phosphopantethine, and NADPH in fatty acid synthesis malonyl coa provides two carbon units to each elongation cycle. NADPH serves as a reducing agent. Malonyl coa also inhibits a futile cycle because fatty acid utilization while fatty acids are being syntehsied. the relationships between fatty acid synthesis and pentose phosphate pathway NADPH is required for both fatty acid synthesis from acetyl-CoA and the regeneration of glutathione catalyzed by glutathione reductase. The pentose phosphate pathway (PPP) is thought to be the major source of NADPH produced at the levels of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase. the regulation of fatty acid synthesis by metabolic stages and biochemicals Chain elongation on fatty acid synthase complex produces homo-dimer. Syntehsis of palmitate on fatty acid synthase complex. The first cahin elongation cycle involes malonyl coA prviding two carbon units. NADPH serves as a reducing agent. Thuiesterase cleaves bond to produce 16 carbon chain. Thioesterase can also produce shorter cahin. The body can also syntehsize fatty acids with cahin leghtn longer than 16 carbons by using proteins embedded in ER membrane. Poly-unsaturated fatty acids can be syntehsized by using various desaturates and elongases. Humans lack enzymes to introduce double bonds between C10 and w-carbon wheras the plants can. That si why essential fatty acids received from diet are important because ethey ahev double bonds beyond the carbon 10 space. Fatty acid synthesis active in the fed state. Pyruvate dehydrogenase and acetyl coa carboxylase needed for fatty acid synthesis indced after a high carbohydrate meal and are active when insulin is high. the intracellular site, key enzymes, and the limitations of fatty acyl chain desaturation Triclosan kills broad spectrum of bacteria and yeasts by inhibirting enoyl-acyl carier-protein reductase which is necessary for fatty acid synthesis in germs. Therefore, tricosalan found in toothpaste, laundry soaps, and cosmetics. the key reactants, subcellular location, major tissues, and rate limiting enzymes associated with cholesterol and bile acid synthesis Cholesterol can be obtained from the diet or synethsized in the body. The conversion of HMG-CoA to mevlonate is the rate limiting step of cholesterol syntehis. HMG-CoA reductase is the rate limiting enzyme. Regulation of HMG-CoA reducatse acitivty through transcriptional control, regulation by proteolysis, and regulation by phosphorylation. Cholesterols synthesized in liver and transported to other tissues visa VLDL then IDL and LDL. Bile salt synthesis 7a-hydroxylase is the rate limiting enzyme in the bile acid synthesis pathway. The conversion of cholesterol to bile salts is the only practical means of removing cholesterol from the body and this conversion occurs only in the liver. the regulation of cholesterol and bile acid synthesis by metabolic stages and biochemicals Bile acids (including conjugated bile acids) that are made from cholesterol by human liver are called primary bile salts. Conugation lowers the pKa of bile salts and makes them better emulsifying agents. Primary bile salts are made directly from cholesterol by human liver. Bile acids are stored in gallbladder. Upon stimulation are secreted into intestine to aid in digestion. the inhibition of cholesterol synthesis by statins, and its underlying mechanism Statins are competitive inhibitors of HMG-CoA reductase and cholestyramine is a bile salt sequestrant. Statins\' primary mechanism of action is through the competitive, reversible inhibition of HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis.  the importance of enterohepatic system Everyday we go through process to get rid of cholesterol. Goes from cholestrrol in liver to bile salts. Then to gall gladder then to fat digestion where it leaves as feces or goes back into liver. the difference between LCAT and ACAT Both have same function of turning cholesterol into cholesterol esters. LCAT works in blood and ACAT in cell. the difference between primary and secondary bile acid Primary bile salts made in liver. After secretin into intestie, primary bile salts may be deconjugated and dehydroxylated by the bacterial flora, forming secondary bile salts. Secondary bile salts such as lithocholic acid are more non polar and thus readily resorbed. Secondary bile salts more prone to excretion. To know the starting materials for sphingolipid synthesis and what would happen if those sphingolipids cannot be degraded Sphingosine received from reactions on the cytoplasmic face of endoplasmic reticulum in all cells. Sphingosine derived from condensation of palmitoyl CoA and serine. Sythesis of sphingomyelin catazylex by sphingomyelin synthases. To know the cause and some examples of sphingolipidosis Sphingolipid diseases include Niemann-Pick disease, tay sachs and gaucher's disease. Niemann-Pick leads to a buildup of fat in cells and causes cell dysfunction. Sphingolipidsoses have accumulation of particular sphingolipids n cells of afflicted indisivuals. Missing or defective enzyme that plays a role in degradation of sphingolipids. To know the importance of the degradation products of phosphoacylglycerols , particularly, phosphatidylinositol DAG and IP3 which are degradation products of glycerolphospholipidsa re known as second meessengers. the structures, compositions, major functions, and the site of synthesis of plasma lipoproteins Triglycerides, cholesterol, cholesterol esters, and phospholipids form non-covalent aggregates with proteins forming a complex known as a lipoprotein. A lot of triaglycerols found in chylomicrons and VLDL. LDL has a lot of cholesterol esters. HDL has a lot of proteins. how plasma lipoproteins are metabolized The triglycerides carried in VLDL are metabolized in muscle and adipose tissue by lipoprotein lipase releasing free fatty acids and IDL are formed. The IDL are further metabolized to LDL, which are taken up by the LDL receptor in numerous tissues including the liver, the predominant site of uptake. the manner in which lipids are transported in the plasma Cholesterol uptake by receptor mediated endocytosis. LDL-receptor present in liver and other tissues. LDL receptor binds LDL, VLDL, IDL, and chylomicron remnants. LDL receptor binds LDL particles. the function of apoprotein CII and B100 C-II is activator of lipoprotein lipase. B100 is structural and is a ligand for LDL receptor secretion of VLDL. the function of LDL receptor, lipoprotein lipase, LCAT, and ACAT LPL -- involved in processing of chylomicrons and VLDL. Stimualted by C-II and insulin. If there is a deficiency of LPL or apo C-II increases chylomicrons and VLDL in plasma. Hepatic lipase -- also called hepatic triaglyceride lipase (HTGL) converts IDL to LDL. LCAT -- catalyzes transfer of long chain fatty acids to cholesterol, forming cholesterol esters. In the blood. ACAT -- intracellular enzyme that esterifies cholesterol. Occurs in cells. the reasons why HDL is considered "good cholesterol" and LDL "bad cholesterol" High HDL helps protect against heart disease. High LDL puts you at risk of heart disease. the relationship between oxidized cholesterol and atherosclerosis LDL can cause damage to endothelial cells in bblood vessels. Formation of foam cells is first step in atherosclerosis. Oxidized LDL can cause endothelial damage which recruits macrophasges. Macrophasges take up oxidized LDL to form foam cell. When the foam cells are substantial, they form fatty streaks. Fatty streaks cause endothelial damages. These growth factors cause proliferatio and migration of smooth muscle cells to the intimal. Layer of the arterial wall. Calification forms. When area ruptures and hemorrhage of plaque occurs, a blood clot or thrombus is formed, which further blocks the blood vessel and causes myocardial infaraction. Statin inhihibipion of cholesterol synthesis works by down regulating inctrcllular cholesterol and up regulating LDL receptrs. Know the structures of dietary sugars and their component monosaccharides. Carbohydrates are either polydydroxy aldehydes or ketones. Must have 3 or ore carbons to be a carbohydrate. Trioses are the smallest monosachharide and categorized by aldehyde group or etone group. An aldehyde is an organic compound in which the carbonyl group is attached to a carbon atom at the end of a carbon chain. A ketone is an organic compound in which the carbonyl group is attached to a carbon atom within the carbon chain. Galactose is ana epimer of glucose. This mena sthere are different configuattion of atoms around one of several asymmetric carbon atoms present. Monosachharides with greater than 5 carbons cyclize in aqueous solutions. Glucose, fructose, and galactose are monosaccharide components of dietary cabohydrates. Dietaary carbohydrates to know Lactose is a galactose attached to glucose at B-1,4 Sucrose is glucose attached to fructose at a-1,4 Lactase, sucrase, amylase, and amylase and isomalatse are enzymes to brea down tehse disaccahrdies. Understand what is unique about the structure of sucrose, and why it is the obligatory precursor of dextran in oral plaque. Sucrose is a glucose donor for oral dextran. The glucose in oral dextran is derived from sucrose. Dextrans in plaqye are polymers of glucose with a-1,3 and a-1,6 glycosidic linakages. Thet are water insoluble. Humans do not have the enzymes to degrage the a-1,3 glucose linkages. So there is a gorwing glucse tcahin of glucose from sucrose. Causes oral dextrans to build up. Know the structures of dietary starch, cellulose and the dextran of oral plaque, and understand the differences. Amylose and amylopectin are dietary starches. Amylose is glucose attached to glucose at a-1,4 Amylopectin is glucose attached to glucose at a-1,4 and a1-1,6 Cellulose is a polymer of glucose held together by B-1,4 linkages. Cellulose is insoluble becayse all of its -OH groups are involved in H bonds. We don't product enzymes to breakdown cellulose. Know how and where dietary carbohydrates are digested and absorbed, and know the names and locations of the key enzymes involved. Salivary and pancreatic enzymes degrade starch and a-dextrins. Enzymes in the small intestine degrade disaccharides into monosaccharides. Dietary fiber -- carbohydrate that is not readily digestied. Soluble fiber dissolves in water and is broken down by bacteria in small insteistine. Includs oats, beans, fruit.. Insoluble fiber does not dssolve in water and passes through digretive system intact. Includes whole wheat flour, nuts, and beans. Dietary fiber helps reduce rsk of colon cancer, cardiovascular disease. Soluble fiber slows absorption of food and lowers glycemic index. Lowers cholesterol. Insoluble fiber increases frequency of bowel movements. Only monosaccharides can be taken up by digestive tract. Salivary amylase degrades starch into a-dextrins. Pancreatic amylase degrades a-detxrins to trisaccharides. Disaccharides in small intestine degrade dissacharides into monosaccharides. Only monosaccharides are transpsorted into intestinal epithelial cells. Salivary and pancreatic a-amylase breaks down starch in different places. Digestion of carbohyddrates -- lactose intolerance -- causes gas and siarrhea when large amount of milk is consumed. Lactic cid produced by anaerobic bacteria draws water by osmosis into intestinal lumen to produce diahherea. Causes gas. Know how glucose is transported into and out of intestinal epithelial cells, and in and out of other cells in the body. There are two types of glucose carriers. 1. Passive (GLUTs): transport follows the concentration gradient. 2. Active (SLGTs): transport against the concentration gradiant coupled to favorable gradient for sodium. Monosachharides are absorbed in the small intestine by SGLT1 and GLUT5 (luminal side) and released into the blood via GLUT2 (blood side). SGLT1 for glucaose and galactose. GLUT5 for fructose. SGLT1: couples glucose and galactose transport to favorable Na+ uptake. This is a sodium linked glucose transporter. Monosachharidge transport into the cells is mediated by passive GLUT transporters. GLUT2 is in the small intestine, pancreas,liver and is a glucose sensor because its Kt (Km equivalent) is typically higher than blood gluocose levels. Insulin directly promotes glucose uptake in adipose, skeletal and heart muscle by increasing expression of GLUT4 at the cell surface. Know the major tissues that store glycogen and the different functions of glycogen depots in liver and skeletal muscle. In muscle and most tissues, glycogen is a fuel source for generation of ATP in the cell. In liver, glycogen serves as a source of glucose for other tissues. More glycogen in well fed state than in starvation. Know the structure of glycogen. Glycogen is the animal storage form of glucose with glucose linked together in a-1,4 and a-1,6 glycolisidic bonds. Glycogen allos for large amounts of glucose to be stored in the cell. Know how glucose is converted to glycogen. Glycogen synthesis requires: a primer (glycogenin), UDP-glucose, glycogen synthase (rate-limiting step), and branching enzyme. Glycogen synthase is the rate limiing step and requires a branching enzyme for the rate limiting step to work. Know how glycogen is degraded and the products of glycogen breakdown in liver and muscle tissue. Glycogenolysis products are glucose-1-phosphate (major) and glucose (minor). Glycogen phosphorylase breaks a-1,4-linkages with a phosphate (rate limiting); the debranching enzyme uses water to break a-1,6-linkages. Know how glycogen synthesis and glycogen breakdown are regulated in liver and muscle tissue. Liver glycogenolysis occurs in the fasting state and releases glucose to the blood. Glucagon and epinephrine increase glycogenolysis by increasing glycogen phosphorylase activity and decreasing glycogen synthase activity. In fasting state, glucose storage sites called glycogen need to be broken down to get more glucose in the blood. Muscle glycogenolysis provides glucose for glycolysis and is stimulated by epinephrine, increases in AMP, and Ca2+. When glucose is need for glycolysis, then glycogen storage sites are broken down to provide the glucose in muscle. Insulin promotes glycogen synthesis in liver and muscle by increasing glycogen synthase activity and decreasing glycogen phosphorylate activity. Glycogen synthase synthesizes glycogen. Glycogen phosphorylase breaks down glycogen. Understand the role of gluconeogenesis in glucose homeostasis and where it occurs. Gluconeogensis helps maintain blood glucose during fasting; primarily in the liver. Blood glucose is tighly regulated. It is important to keep blood glucose level at normal level. Insulin is hormone and tells us that we are fed. Glucagon and stress hormones when we are not fed. During fasting, increased glucagon, epinephrine. Favor glycogenolysis, gluconeogenesis, and lipolysis. Know the major carbon sources for gluconeogenesis in the liver and how they are converted to glucose. Precursors are amino acids (main source) and glycerol (minor). Glycerol released from lipolysis of triglucerides. Acetyl CoA can not be converted into glucose. So, fat is not a carbon source for gluconeogenesis. Understand the role of fatty acids as the primary fuel supporting gluconeogenesis. Energy source for glucoenogenetis is fatty acid oxidation and not a carbon source. Know the relationship between glycolysis and gluconeogenesis, the steps that differ between the two pathways and how they are regulated. Reciprocal control: F26BP increases glycolysis and decreases gluconeogenesis. Insulin increases F26BP. Glucagon and epinephrine decrease F26BP. Reciprocal regulation in the liver. When glycolysis is increased, gluconeogenesis is decreased. When gluconeogenesis is increased, glycolysis is decreased. Enzymes unique to glycolysis: Step 1: Hexokinase, Glucokinase 2. PFK-1, Step 3. Pyruvate kinase Enzymes unique to gluconeogenesis: Step 1: pyruvate carboxylase and PEPCK, Step 2. F-1,6-BPase, 3. Glucose-6-Phosphatase (liver only) For gluconeogenesis, conversion of pyruvate to PEP requires pyruvate carboxylase, PEPCK, and 2 ATP equivalents. Which of the following enzymes of the Pentose Phosphate Pathway requires thiamine as a cofactor? transkelotase In the liver, insulin stimulates glycolysis by promoting PFK2 to produce F-2,6-BP. Glucagon and epinephrine inhibit F-2,6-BP formation and stimulate its breakdown. Regulation of glycolysis and gluconeogenesis in the liver by allosteric modifiers and protein phosphorylation. Regulation by altering enzyme expression. Glycolysis is favored in fed state with elevated blood glucose, blood insulin, liver F26BP, and AMP. Gluconeogeneis is favored in the fasting state with decreased blood glucose, blood insulin, liver F26BP, and AMP. Predict how cellular metabolites, hormones and blood glucose levels control glycolysis and gluconeogenesis. Fed state: Increased insulin/glucagon (Insulin relative to glucagon) increased glucose utilization (glycolysis). Increased synthesis of biomolecules and fuels (glycogen, fat, protein). Fasting state: Decreased insulin/glucagon, Increased glucagon and stress hormones (epinephrine, cortisol). Decreased glucose uptake (adipose, muscle). Decreased glucose utilization (liver). Increased mobilization of fuels (glucose output liver, lipolysis, protein degradation/release of amino acids). Starved state: Decreased protein degradation to protect organs (decreased urinary nitrogen). Gluconeogenesis is reduced, but still occurs. Increased reliance on fatty acids by most tissues and ketone bodied by the CNS. Explain the function of the Pentose Phosphate Pathway: NADPH is used for: biosynthetic reactions; to prevent oxidative damage to cells; to generate reactive oxygen species for phagocytosis. Ribose for nucleotide biosynthesis. Oxidative phase: 2 NADPH, CO2, and ribose-5-phosphate Non-oxidative phase: fructose-6-phosphate, glyceraldehyde-3-phosphate Oxidative phase is irreversible, no ATP generated, G6PDH is rate limiting and is inhibited by NADPH requires NADP+ for activity. Non-oxidative phase is reversible, interconversion of 5- and 6- carbon sugars, ribose-5-phosphate consumed in growing cells; ribose-phosphate feeds into glycolytic intermediates when only NADPH is needed. Functions of NADPH: reductive biosynteis (anabolism) reduces glutathione (scavenges ROS), generate ROS in phagocytes. NADPH is a strong reductant. Reduced glutathione (GSH) is important in cells to maintain a reducing environment and degrade ROS. Ribose-5-phosphate: sugar component of nucleotides (synthesis of DNA/RNA, cell growth); ATP and co-factors. Role of pathway in red blood cells: scavenges ROS. Phagocytosis and the pentose phosphate pathway -- penstose phosphate pathway provides NADPH for repiratory brust. Needed for phagocytoic cells to respond to an infectious agent and rapidly consume O2 to produce reactive oxygen species. The ROS then ehlp to kill invading pathogens. Describe the consequences of glucose-6-phosphate dehydrogenase deficiency Pathway of glucose-6-phosphate dehydrogenase: hemolysis in times of oxidative stress. Role of pathway in phagocytosis: generates ROS via NADPH oxidase which consumes oxygen and NADPH. ROS generated are cytocidal. Symptoms are revealed by oxidative stress and can be caused by antimalarial agents, infections, and fava beans. All bad for glutathione defense mechanism. Explain how glucose forms UDP-sugars and their roles in the synthesis of lactose, glycoproteins, glycolipids, proteoglycans and glucoronides. Metabolic fate of UDP-glucose (glucose donor for glycogen and glycoproteins, epimerization of glucose/galactose). Role of transferase enzymes in UDP-sugar metabolism (glycoproteins, galactose metabolism. Formation of UDP-glucuronate -- (proteoglycans, bilirubin diglucornide, steroid degradation). UDP glucuronate pathway is important to drug detoxification, exrection of bilirubin, and steroid excretion. Explain how fructose and galactose are converted to intermediates of glucose metabolism and how their fates parallel that of glucose Metabolic fates of galactose and fructose (converted to glycolytic intermediates, fructose mainly metabolized in the liver. Dietary fructose can be metabolized to glycolytic intermediates primarily in th liver. Metabolism of fructose bypasses key regulatory steps in glycolysis. Bypass PFK-1 and no ATP feedback inhibition. High levels of fructose can lead to liver damage, lacti acidosis, and fatty acid synthesis in the liver. Describe the relationship between the Polyol Pathway hyperglycemia, sorbitol and ROS. Polyol pathway converts glucose to fructose, consumes NADPH, sorbitol is elevated with hyperglycemia. For the pylol pathway for fructose synthesis, NADPH is consudened. Buildup of surgar alcohol and consumption of NADPH in the lens, nevre, and glomerulus in diabetics may contribute to tissue damage. Sobitol accumulates in most tissues. Depeletion fo NAPDH results in accumulation of ROS. In pylol pathway, glucose converted to sorbitol. Cell tehn converts sorbitol to fructose. Uses NADP+ and reduces to NADH to get fructose. Only activated when high concentrations of glucose. Understand sources and metabolic fates of amino acids: Metabolic fates of amino acids include protein synthesis, generation of carbon skeletons and N-containing compounds. Essentially free amino acids can be metabolized to generate glucose, ketone bodies, or carbon skeletons to drive the TCA cycle. Essential amino acids and their sources Essential amino acids are received from diet and body cannot syntehesize on its own. Include LILTVToPMHA which si lysine, isoleucine, leucine, threonine, valine, tryptophan, penenylalanine, methionine, histidine, arginine. Nonesential amino acids are still needed but can be syntehesized by body. Include the neumonic almost all girls go crazy after getting taken prom shopping which includes serine, glycine, cysteine, alanine. Essential amino acids from diet cannot all be gotten from plant diet. Vitamins B12 and D are not found in plant based det. For plant based diet, vitamin supplments are critical to prvent disease (like anemia). How amino acids can be used as fuel to drive energy production Most amino acids are glucogenic. Menas that carbon skeletons contribute to formation of new glucose. Every amino aci glucogenic except for lysine and leucine. The main precursors of gluceogensis is lactate, glycerol, and alanine. Some amino acids can form ketone bodies. TILT pneumonic threonine, lysine, isoleucine, and tryptophan to form acetyl coa. Leucine to form HMG CoA. Phenylalanine, tyrosine to form ketone bodies. Amino acids are important for maintiang blood glucose levels in fasting Understand key steps in urea cycle Conversion of amino acids to carbohydratre results in production of ammonium, which must be converted into urea. Protein digestion: proteins must be broken down to near-free amino acid form to be absorbed. Exoprotreaases cut the amino or carboxyl terminal amino acid off of the protein chain. Endoproteases recognize specific amino acids and cut at that site. Pepsin vs trypsin protease differences. Pepsin: stomach, endoprotease Phe, Tyr, Glu, Asp, pepsinogen, by acid, by pepsin, first protease Trypsin: intestine, endoprotease, lys, arg, trypsinogen, enterokinase, activates other zymogens. Amino acid transport is done by sodium linked carriers. To use carbon skeletons we must dispose of nitrogem. Once amin o acids get into cell they drive protein synthesis but mitrogen has to be removed. It is removed during urea cycle. The amine group can be removed or transferred by an aminotransferase. PLP and vitamin B6 needed for aminotransferase.Ultimately glutamate dehydrogenase (GDH) rea removes te amino group from glutamate. Generates alpha-ketoglutarate and ammonium (NH4). Precursors for the urea cycle are 1 nitrogen from ammonium and 1 from aspartate. Final product for urea cycle is urea. Urea cycle starts in mitochondria of liver. Bicarbonate joins with free ammonium to make cabamoyl phosphate. Hooks up with ornithine to make citrulline. Citrulline leaves mitochondria. In cytosol. Hooks up with aspartate. Loses fumarate to make arginine. Arginase makes urea from arginine. If cant package ammonium into urea, then ammonium accumulates into blood stream and causes problems. Urea cycle is drivn by N-acetyl glutamate. Urea production increases in fasting. Understand the roles of folate (B9) and vitamin B12 in metabolism, and the major sources of single-carbons in the folate cycle, and their role in nucleotide biosynthesis Folate and vitamin B12 serve as carriers of carbon atoms in several key metabolic pathways, including nucleotide biosynthesis; deficiencies can lead to disease (anemia, etc). Serine and glycine are key sources of carbon for folate. Folate is critical for nucleotide biosynthesis. Metabolism of serine and glycine can result in transfer of a single carbon to folate. Folate then transfers the carbon to help syntehesize pruine nucleotide (adenosine. Guanosine), and deoxythymidine (dTMP). Folate can also trnafer a carbon to vitamin B12 which can transfer carbon to other pathways. FH4 is the active form of folate and can accept cabon atom from serine, glycine, etc. The carbon from FH4 must be transferred for either nucleotide biosynthesis or B12 methylation. Potential roles of B-vitamins in oral health and symptoms linked to deficiencies Folate deficiency leads to megaloblastic anemia. Folate ound in leafy green vegetables. Megaloblastic anemia is characterized by decreased number of mature red blood cells and accumulation of nucleated precursor cells (megaloblasts). This is because of key r0le of folate in nucleotide synthesis required to replicate DNA for blood cell maturation. Low folate in first few weeks of pregnanc can cause neural tube defects such as spina bifida. Important to eat folic acid during pregnancy to reduce chance of neural tube defects. Vitamin B12 deficincy also leads to megaloblastic anemia. Vitamin B12 found exclusively in animal products such as meat, diary products, nd eggs. B12 linked to folate dependent metabolism so results in megablostic anemia. In the absence of B12, FH4 is trapped in this corm of CH3 and cannot be recycled known as folate trap. Need to eat foods with vitamin B12 or else you may get pernicious anemia which is caused by destruction of pairietal cells in stomach, leads to deficiency due to poor absorption of dietary B12. **Pernicious anemia**, one of the causes of vitamin B12 deficiency, is an autoimmune condition that prevents your body from absorbing vitamin B12. All dividing cells depend on nucleotride biosynthesis which in turn requires folat ena dB12 for important steps. Folate and B12 deficincies in dentistry related to glossitis (inflammation of the tongue), angular chelitis (inflammation of corners of mouth), and recurrent apthous stomatitis (mouth ulcers). B12 deficicncy can be linked to heart disease and demyelination. B12 deficicny can occur even when nutrition is otherwise ok because needs to be secreted and absorbed. Understand key steps and major amino acid precursors of selected neurotransmitters Neurotransmitters are synthesized from specific amino acid precursors, and neurotransmitters can be impacted by activity in these pathways. B12 transfers methyl group to generate SAM, a key methyl group donor. SAM donates a methyl group for synthesis of some neurotransmitters. Ex. norepinephrine turns into epinephrine with SAM. Acetylserotonin turns into melatonin with SAM. Seratonin and melatonin derive from tryptophan. Catecholamines (including norepinephrine and epinephrine) from phenylalanine/tyrosine. Histamine from histidine. Nitric oxide from arginine. Histimine is made and released by mast cells. Regulates sleep-wakeflness. Catecholmaine is made from Phe and Tyr. SAM used to form epinephrine from noepinephrine. Epi nand norepi used as transmitters throughout CNS and in the adrenal medulla they help in fiht or fligh reactions. Serotonin and melatonin synthesis from tryptophan.Serotonin is 5HT which in the pineal gland is turned into melatonin. Released at night. Critical in regulating circadian rhythm. SSRIS and oral health. Low serotonin linked to things such as drepressin, anxiety, obsessive/compulsive disorder. SSRI can enghace aeffect of serontin by increasing lifetime in synapse. Examples called Fluxoetine (Prozac), Sertaline (Zoloft), and Paroxetine (Paxil\_. These drugs can can xerostomia (dry mouth) which increase rick of dental carries and other issues in the mouth. Glutamate = excitatory neurotransmitter. GABA = inhibitory neurotransmitter Nitric oxide synthesis from arginine. By relaxing arterial smooth muscle, NO acts as vasodilater which helps lower blood pressure. Creatine biosynthesis sinvolvees arginine, glycine, and methionine (SAM). Creatine produces ATP in the cytosol and is an important energy source in mucles and brain. Nucleotide synthesis can be targeted by anti-cancer drugs like methotrexate. Purines are synthesized from glutamine, glycine, aspartate, and carbon from FH4. Pyrimidines are syntehsised from glutagmine, astpartate, and carbon for T from FH4. FH4 critical for nucleotide production. Understand mechanisms underlying disorders of amino acid / nitrogen metabolism Branched chain amino acids are deaminated and metabolid in muscle and brain to drive ATP production. Luecine, isoleucine, and valine are branched chai amino acids because you have to branch out to liv and this spells out liv. Amine groups are transferred to pyruvate to generate alanine. Alanine can be released intoblod stream and then absorbed by liver. In the liver, alanine is broken down to pyruvate. Excess NH3 drives formation of urea. Transamination generates alpha ketoacids. Alpha ketoacids must be metabolized by alpha ketoacid dehydrogenase. Cabrn skeletns metabolized to form propionyl coA -\> succinyl coA or ketone bodies to drive TCA cycle. Maple syrup urine disease -- ereditary variant causing decrease in alpha-ketoiacid dehydrogenase activity. Comes from sweet odor due to accumulation of branched cahin alpha ketoacids and by producs. Treatment requires low protein diet to limit levels of branched chain amino acids. Neumonic maple syrup cant process alpha ketoacids and maple syrup is not processed and is fresh. PKU - Catecholamine biosynthesis is where conversion of phenylalanine to tyrosine depends on phenylaline hydroxylase. PKU is whe phenylalaniene hydroxylase is defective. Phenylalanine cannot be converted to tyrosine. Phe is converted to other products which accumulate to toxic levels. Diet must restrict levels of phenylalanine with supplementation of tyrosine. Avoid nutraweet which contains phenylalanine equivalents tand must be avoided. Neumonic PKU sounds like PSY and have too much fun with phenylalanine so cant convert to tyrosine and be responsible car driver. Alkaptonuria - Phenylalanine and tyrosine degradation linked to diseases. One is alkaptonuria where defcect in homogentisate dioxygenase (in tyorisne degradation pathway). Leads to accumulation of homogentisate in tissues, bbone, urine. Urine turns black after exposre to air. Alkapton can accumulate in cartilage, bone, sclera. Can lead to arthertitis, damage to heart valves in kindeys, and sialothiasis. Stones in salivary gland. Neumonic -- alpacas tired out so tyrosine degradation affected. Alpacas pee and it can turn black with this tyrosine degradation. Homocysteine metabolism -- homocysteine is an intermediate metabolite in the generation of SAM. Metabolized to cysthionine. Depends on PLP which is derived from dietary vitamin B6. Homocystinuria or HCU is a defect in cystathionine synthase. Leads to accumulation of homocysteine in blood and urine. Can result in cardiovasculat diseases and thromboemolisms, pectus excavatum, and lens dislocation. Treated by high doses of vitamin B6 aimed at maximizing activity of defective enzyme. Also treated by decreaseing intake of methionine, increase intke of B12, folic acid to metabolzie HC through mehionin synthase pathways. Mneumonic homocysteine cant be metabolized properly and causes many issues with homocysteine buildup. Gout- elevated pruine degradation can lead to gout. Major purine degradation product is uric acid formed by xanthine oxidase. Insolubility of uric acid leads to inflammation/ gout. Allppurinol can inhibit xanthine oxidase and is a treatment for gout. Gout happens when unpure so purines are degrading and becoming unpure. Understand the role of amino acids in metabolism during infection and wound healing underlying the hypercatabolic state Physical trauma or critical illness results in a hypercatbolic state, in which amino acid metabolism is altered to drive immne cell production and fight infection. Cells of immune system receive top priority in terms of utilizatip of amino acids Hypercatabolic state is characterized by increased fuel utilization and negative nitrogen balance. Can occur following trauma, surgery or illness. HS associated ith eleveated levels of cortisol. Cortisol release stimulates glucose/ fatty acid metabolism. Resulting mobilization of protein, lipid, and carbohydrates serves to maintain normal tissue function if diertay intake low. Support requiremnts of immune response and wound healing. While HS is associated with decreased food intake, its metabolic effect is distinct from starvation. HS is characterized by negative nitrogen balance; protein breakdown and nitrogen excretion are greater than dietary protein intake. Amino acids directed toward building immune system to promote recovery. Amino acids important for building proteins, cellular energy, and providing raw material for synthesis of neurotranmitters, hormones, and nucleotides. Some amino acids can be synthesized in our bodies (ultimately from glucose) others must be obtained from dietary proteins which are digested by peptidases. Metabolism of amino acids can generate ammonium which is packaged into urea via the urea cycle. Vitamin B12 and folate (vitamin B9) are both important cofactors in nucleotide biosyntehis which is critical for production of blood cells and other dividing cells. Several amino acids are precurors of important nurotransmitters. Puurine and pyrimidine synthesis involves raw materials form sveral key amino acid precursors as well. Disruption of amin acid metabolism can lead to accumulation of toxic molecules resulting in disease. **Discuss why and when the body needs to switch from storing to mobilizing fuels, and from glucose to fat use in most tissues.** **When dietary fuel is available we store as much as we ca. When dietary fuel is gone we mobilize fuel stores. We need to be able to switch between making and breaking stored fuels. Insulin and glucagon/catecholamines are master controllers of fuel storage, fuel mobilization, and fuel switching. Insulin/glucagon are regulated by blood glucose concentrations. If glucose if plentiful, we use and store it. If glucose is gone we mobilize fuel storage sites and make more fuel. Insulin promotes fuel storage after a meal while glucaon mobilizes fuels and helps maintain blood glucose levels during fasting.** **List the major effects of insulin and glucagon on liver, adipose tissue, and muscle.** **Insulin -- stimulates glucose storage as glycogen in muscle and liver. Stimulates fatty acid synthesis and storage after a high carbogydrate meal. Stimulates amino acid uptake and protein synthesis.** **Glucagon -- Activatees gluconeogenesis making new glucose and glycogenolysis breaking down glucose storage sites (liver) during fasting. Activates fatty acid release from adipose tissue.** **Describe the approximate time course of fluctuation of glucose, insulin and glucagon levels.** **Actual duration of post meal glucose/insulin pulse depends on how fast carbohydrate is absorbed by gut. Glucose stimulates insulin release after a meal. Insulin/glucose inhibits glucagon release. Glucagon is stable as long as insulin and glucose are above its baseline. Glucose and insulin parallel each other on time course graphs. Glucagon and insulin have opposite effects in blood.** **After a high protein meal with no carbohydrates, there is only a small increase in insulin which stimulates some amino acid uptake and protein synthesis. Also larg increase in glucagon controls glucose and fatty acid metanolism. Balance of insulin and glucagon keeps glucose levels steady.** **Discuss the regulation, sources and mechanisms of action of insulin and glucagon** **Insulin and glucagon are major inhibirots of each other.** **Insulin and glucagn respond primarily to lucose levels in the blood but can also affect metabolic processes in liver, adipocyte, and skeletal muscle.** **Insulin and glucagon are polypeptide hormones. They are short lived. They act at the cell surface of tehir target cells.** **Insulin receptor is a kinase receptor activating numerous pathways. It also activates protein phosphatase 1, a signifant effect is to dephosphorylate enzymes that are substrates for protein kinase A.** **For glucagon, the second messenger mediates all the effects of glucagon in tha target cell. Glucagon activates G protein which activates adenyl calse which activaes cAMP. cAMP inhibits regulatory subunits. Get activation of PKA. Adds phosphate group to enumes or other intrcellular proteins. Results in glucagon phosphorylates proteins.** **Important summary** **Insulin --\> phosphodiesterase and portien phosphatase-1 -\> dephosphorylation of enzymes** **Glucagon -\> cAMP -\> PKA -\> phospohorylation of enzymes** **Insulin stimulates glucose transport only in adipose and muscle. Not in RBCs and brain because need a constant supply of glucose in all nutritional states. Not in liver becayse importaing glucose in fed state and exporting glucose in fasted state. Must have glucose tranporters in all nutritional states.** **Muscle and adipose can run on fat during fasting and rest. Glucose can be spared for brain and RBC that must run on glucose Glut4 glucose transporters ysed to move glucose in muscle and adipose.** **Explain how the downstream activities of insulin and glucagon work antagonistically as a binary switch.** Phosphorylation activates some enzymes and inactivates others. This is the master switch of fuel metabolism. Insulin dephosphorylates key regulators enzyme. Glucagon phosphorylates key regulatory enzymes. Pneumonic device ID and GP for insulin dephosphorylates and glucagon phosphorylates. Identify the sources of reactive oxygen species NADPH oxidases generate ROS. NADPH oxidates used to transfer electrons to dissolved oxygen and generate superoxide. Superoxies may be used to destroy phagocytosed pathogens or in cell signaling pathways. NADPh is formed in the penstose phosphate pathway and used for this. Mitochondrial ROS formed in the electron transport chain. Compelx II and II electron can form superoxide instead of flowing down cahin, When O2 binds compelx IV thre ransfer of electrons is direct and no ROS is formed. O2 is ultimately reduced to H2O in ETC. Macrophages/neutrophils weaponized ROS. In presence of microorgamisms, macrophages and neutrophils increase upatek O2. Rapid uptake O2 and rlease of Ros from cells termed oxidative or respiratory burst. Cellular NADPh oxidases (NOX) actiaved and transfer electron from NADPH to form O2- (superoxide\_. List the reactive oxygen species When an atom/molecule loses electrons it is oxidized. When an atom/molecule gains electrons it is reduced. Free radicals are defined as molecules bearing an unparired electron and RS are highly reactive. Oxygen can accept 4 electrons and be reduced to H2O. Oxygen accepts 1 electron to form superoxide. Oxygen can accept 2 electrons to form hydrogen peroxide (H2O2). Oxygen can accept 3 electrons to form hydroxyl radical. The three primary species, the superoxide anion (O2 ‒), hydrogen peroxide (H2O2) and the hydroxyl radical (HO ), are called reactive oxygen species because they are oxygen-containing compounds with reactive properties. O2 ‒ and HO are commonly referred to as "free radicals". Describe the inactivation of ROS both enzymatically and non-enzymatically For enzymatic cellular protection, superoxides are converted to H2O2 by superoxide dimuatases. Family So1 or So2. These enzymes contain Zn+, Cu+, or Mn2+. Need enough of tehse metals to ensure that cell is protects and speroxides are not just staying in cell. Generated H2O2 is then rapidly converted to H2O by catalase. Superoxide dimuates can only wok if have zinc and copper. Need these metal to change superoxides into H2O2 and then H2O. For non-enzymatic cellular protection, Glutathione made of Glu-Cys-Gly is considered the key cellular antioxidant in organisms. Glutathoine is a reducing agent that can donate electrons to neurtrlize ROS. Works with glutathione peroxidases and NADPH from pentose phosphate pathway to neutralize ROS. Also non-enzymatic anti oxidatnt is vitamin E. Get through the diet anti-oxidant primarily preventing lipid peroxidation. Also non-enzymatic factor Vitamin B3 Niacin from diet helps as an antioxidant to neutralie ROS.Also non-enzymatic anti-oxidant Vitamin C (ascorbic acid\_ is a free radical scavenger (anti-oxidant) in aqueous compartments0. Scurvy is a vitamin C deficicency and defect in collagen cross linking. Proline and lysine group issue for scurvy. Vitamin E, Ascorbic acid (C), and Niacin (B3) all work to prevent damage. Reversal of entire oxidation is dependent on NADPH. Identify the macromolecules damaged by ROS DNA, lipid, and proteins all affected by ROS. ROS can react with DNA and RNA to cause base damage or strand breaks. Ros induced base damage is conversion of Guanine to 8-oxoG, a mutogenic lesion. ROS induced damage is DNA double stranded breaks. Lipid peroxidation of a polyunsaturated fatty acid. Antioxidants needed to terminate action of lipid peroxidation or by glutathione peroxidase activity. Protein oxidation. ROS react with thiol groups (met and cys) and pro, arg, his, NH2 groups. Can cause cross-links, aggregation, misfolding, proteosome dysfunction. Also lipofuscion formation of brownish pigment in cells, sign of caabolic dysnfcuntion, and age spots due to protein oxidation/ Discuss the role of ROS in periodontal disease Metal ions accoaisated with antioxidant enzymes including Cu, Mn, and Zn, signigaicntly decreaed in periodontitis group compared to control. This suggests redox environment favoring oxidative stress instead of ROS being removed by antioxidant enzymes in saliva of periodontal patients. Superoxide levels measured in aliva and serum. SODS decreased in saliva and serum from periodontal group compared to control group. More important role for local SOD than I n systemic circulation in control of redox status in periodontitis. Local redox imbalance surrounding the teeth contributes significantly to the onset and progression of periodontal diseases. Reactive oxidant species found in excess in periodontal patients and not cleared out by antioxidant enzymes. SODS are important and in healthy patients help clear out reactive oxygen species. Describe the effects of insulin insufficiency on metabolic hormones and metabolism. Increased: glucagon, blood levels of glucose, fatty acids, amino acids, protein breakdown, fatty acid oxidation, gluconeogenesis, lipolysis of triaglycerides in adipose from increased HSL. Decreased: glycolysis, fatty acid synthesis, protein synthesis, lipolysis of triaglycerides n VLDLs and chylomicrons. Compare and contrast Type 1 and Type 2 diabetes mellitus. Type I: People cant produce insulin, susceptible to ketoacidosis. Autoimmune destruction of pancreatic beta cetlls. Age of onset is young. Ketoacidosis is common. Endogenous insulin is low or absent. Beta cells produce little or no insulin. Type II: Tissues resistant to insulin. Associated with obesity. Age of onset is mostly aduts. Ketoacidosis is rare. Endogenous insulin is normal, decreased, or increased. Is most common type in US. Obesity is a common cause of insulin resistance. Initally beta cells produce normal/elevated insulin. Diminshed effects of insulin on target tissues as a result of insulin resistance. Down regulation of insulin receptor. Results in decreased glucose uptake in muscle and adipose. Describe the complications of DM Elevated glucose -- increased glycogenolysis and gluconeogenesis. Decreased glucose uptake by GLUT4 and glycolysis. Increased lipid catabolism -- increased breakdown of triglycerodes in adipocutes due to increased activity of hormone sensitive lipase. Increased B oxidation. Elevated ketone bodies Disrupted lipoprotein metabolism -- increased VLDLs, chylomicrons (LPL) Increased protein catabolism -- Insulin promotes protein synthesis. In its absence, protein breakdown predominates. Insulin helps to stimulate glucose transport in adipose and muscle using GLUT4 transporters. If low blood glucose and insulin, GLUT4 transporters sequeested in. membrane bound vesicles inside cell. Cell takes up less glucose. If high blood glucose and insulin, nsulin stimulates insertion of GLUT4 containing vescibles into the plasma membrane. Cell takes up more glucose. Ketone body synthesis increases with prolonged fasting or impaired insulin. Ketoacidosis is common in type I diabetes because low insulin so a lot of ketone bodies are produced. Insulin inhibits glucagon and insulin inhibits HSL which leads to ketoacidosis. Hyperglycemia - is a condition in which the level of glucose in the blood is higher than normal. Sometimes called "high blood sugar," it commonly affects people who have diabetes mellitus, but it can also develop in non-diabetics. Glucose is the primary source of energy for all cells in our bodies. Hyperglycemia hyperosomolarity syndrome (HHS) - For diabetes type I, lipolysis is unimpended. Elevated fatty acids lead to excess ketogenesis. Excess ketone bodies lead to ketoacidosis. Describe how the polyol pathway contributes for ROS generation and AGEs. High glucose leads to glycation, the non-enzymatic addition of glucse to proteins. Over time glycated proteins become oxidized and crosslinked to form advanced glycation end products (AGEs). Reactive oxygen speices (ROS) promote formation of AGEs. AGEs impair protein function and long term complications associated with tissue damage such as in nerve, kindey, elevated lipoproteins, oral tissues. Hyperglycemis causes depletion of NADPH results in accumulation of ROS which promotes AGEs. Describe the relation between DM and oral health HbA1c percentage reflects the average blood glucose over a period of the past 3 months and can be used to diagnose and montor diabetes mellitus. Most common oral problems associated with poorly controlled diabetes melittus is salivary gland dysfunction (Xeroxstomia\_ which involves a burning mouth sensation, dental caries, oral infection, taste impairment, poor oral wound healing, and periodontal disease. DM1 and DM2 risk factors for periodontitis. DM induces hyper-inflammatory response to periodontal microbiota and impairs repair. Receptors for AGEs mediate hyper inflammatory response. Good dental health can prevent mouth problems and help manage diabetes. Periodontal therapy can improve glycemic control. Understand differences among karyotype, fluorescence in situ hybridization (FISH), and array cGH. A karyotype is a complete set of chromosomes in an individual, organized and displayed in pairs by size and shape. It allows for the visualization of chromosome number (e.g., aneuploidies like Down syndrome, which is characterized by an extra chromosome 21) and large structural abnormalities (e.g., translocations, deletions). Fluorescence In Situ Hybridization (FISH): FISH is a molecular cytogenetic technique that uses fluorescent probes that bind to specific parts of chromosomes. This allows for the detection of specific genetic abnormalities at a higher resolution than karyotyping, such as small deletions or duplications and translocations. It\'s often used for diagnosing specific genetic disorders and identifying chromosomal abnormalities in cancers. Array Comparative Genomic Hybridization (array CGH): Array CGH is a more advanced technique that allows for the analysis of the entire genome simultaneously. It detects copy number variations (CNVs) across the genome by comparing the test DNA to a reference DNA. This method can identify smaller deletions and duplications than karyotyping or FISH and is useful for diagnosing genetic disorders, particularly those with developmental delays and congenital anomalies. Describe the common structural variations of human chromosomes and their associated disroders. Deletions: Loss of a segment of a chromosome can lead to disorders such as: Angelman syndrome -- deletion In maternal chromosome 15. Prader -Willi syndrome -- deletion in paternal chromosome 15. Duplications: Extra copies of a chromosome segment can lead to: Inversions: A segment of a chromosome is reversed end to end. While inversions may not always cause disease, they can disrupt gene function if they break a gene. Translocations: A segment of one chromosome breaks off and attaches to another chromosome. These can be balanced (no genetic material lost) or unbalanced (some genetic material lost). Understand how imprinting can affect expression of disease. Imprinting refers to the epigenetic phenomenon where genes are expressed in a parent-of-origin-specific manner. This can affect disease expression in several ways: Prader-Willi Syndrome (PWS): Caused by the loss of paternal expression of genes on chromosome 15. If the paternal allele is deleted or mutated, the maternal allele (which is normally inactive) cannot compensate. Angelman Syndrome (AS): Arises from the loss of maternal expression of genes on the same chromosome 15. Here, the paternal allele is typically imprinted (silenced). Impact on Disease: Imprinting can lead to different phenotypes depending on whether the mutation is inherited from the mother or father. This is crucial in diseases that are linked to genomic imprinting, as the parental origin of the mutation can dramatically alter the clinical presentation. Become familiar with pedigree nomenclature. A pedigree is a diagram that depicts family relationships and patterns of inheritance for specific traits or diseases. Key components of pedigree nomenclature include: Symbols: Squares: Males Circles: Females Filled symbols: Affected individuals Half-filled symbols: Carriers (for recessive traits) Lines: Connect relationships (horizontal for marriages, vertical for offspring). Generations: Generations are typically numbered (I, II, III) from top to bottom. Proband: The individual through whom the pedigree is initiated (often marked with an arrow). Understand major modes of inheritance, penetrance, expressivity, mosaicism, and anticipation. **Autosomal Dominant:** Affected individuals have at least one affected parent. Traits appear in every generation. Example: Huntington\'s disease. **Autosomal Recessive:** Individuals can be carriers and may have unaffected parents. Trait can skip generations. Example: Cystic fibrosis, sickle cell disaese **X-Linked:** Males and females can be affected, but affected males pass the trait to all daughters and no sons. Mostly affects males (females are carriers). Can skip generations. Example: Duchenne muscular dystrophy Mitochondrial Inheritance: Inherited maternally; all offspring of an affected mother may be affected. Example: Leber Optic atrophy **De novo:** Any disease, ex. autism spectrum disorder Complex: Incomplete penetrance, genetic modifers, environmental modifiers. Penetrance: The proportion of individuals with a particular genotype that express the associated phenotype. For example, if 80% of individuals with a mutation express the trait, the penetrance is 80%. Expressivity: The degree to which a genotype is expressed in an individual. It can vary among individuals with the same genotype, leading to a range of phenotypes. Mosaicism: The presence of two or more genetically different cell lines in the same individual, resulting from mutations during development. This can lead to variable expression of genetic traits. Anticipation: A phenomenon where successive generations exhibit a more severe phenotype or earlier onset of a genetic disorder. Common in trinucleotide repeat disorders like Huntington\'s disease. Know the genetic basis for blood type. Blood types are determined by the ABO and Rh systems: ABO System: Involves three alleles: A, B, and O. A and B are co-dominant (if both are present, the phenotype is AB). O is recessive. Blood type combinations: Type A: Genotypes AA or AO. Type B: Genotypes BB or BO. Type AB: Genotype AB. Type O: Genotype OO. Blood type A has A antigens and B antibodies in plasma. Blood type B has B antigens and A antibodies in plasma. Blood type AB has A and B antigens and no antibodies in plasma. Blood type O has no antigens and A and B antibodies in plasma. Become familiar with the red flags of genetic disease. Multiple affecteds in multiple generations. Extreme or exceptional presentation of common conditions. Bilateral primary cancers in paired organs Multiple primary cancers of different tissues Neurodevelopmental delay or degeneration Developmental delay in pediatric age group Extreme or exceptional pathology pheochromocytoma, acoustic neuroma, medullary thyroid cancer, multiple colon polyps, plexiform neurofibromas, multiple exostoses, most pediatric malignancies Unexpected laboratory values ectodermal dysplasia Description: A group of disorders affecting the development of ectodermal structures, which include skin, hair, nails, and teeth. Features: Hypotrichosis (reduced hair), hypohidrosis (reduced sweating), and missing or abnormal teeth (often conical or peg-shaped). Inheritance: Most forms are X-linked recessive, but autosomal dominant and recessive patterns also exist. Associated Issues: Increased risk of overheating due to reduced sweating. amelogenesis imperfecta Description: A genetic disorder affecting the development of tooth enamel. Features: Abnormal enamel thickness, color, and structure; teeth may be discolored, prone to decay, and sensitive. Inheritance: Can be X-linked, autosomal dominant, or autosomal recessive. Management: Dental treatments to protect teeth and manage sensitivity. hereditary hemorrhagic telangiectasia Description: A genetic disorder that leads to abnormal blood vessel formation, resulting in telangiectasias (small, dilated blood vessels) and arteriovenous malformations (AVMs). Features: Frequent nosebleeds, skin and mucosal telangiectasias, and a risk of internal bleeding (e.g., in the lungs, liver, brain). Inheritance: Autosomal dominant. Management: Monitoring for AVMs and treating bleeding episodes. neurofibromatosis Description: A genetic disorder characterized by the growth of benign tumors called neurofibromas on nerves and skin. Types: NF1: More common; characterized by café-au-lait spots, neurofibromas, and freckling. NF2: Characterized by bilateral vestibular schwannomas (acoustic neuromas) leading to hearing loss. Inheritance: Autosomal dominant. Associated Issues: Increased risk of certain tumors, learning disabilities, and other neurological symptoms. osteogenesis imperfecta **Description**: A group of genetic disorders characterized by fragile bones due to defective collagen production. **Features**: Frequent fractures, blue sclera, dental imperfections, and hearing loss in some types. **Types**: Vary in severity; type I is the mildest, while type II is often lethal in infancy. **Inheritance**: Mostly autosomal dominant, with some forms autosomal recessive. **Management**: Focus on fracture prevention, physical therapy, and in some cases, bisphosphonate therapy. basal cell nevus syndrome Description: A genetic condition predisposing individuals to various neoplasms, particularly basal cell carcinomas (BCCs). Features: Multiple basal cell carcinomas, jaw cysts (odontogenic keratocysts), palmar and plantar pits, and skeletal abnormalities. Inheritance: Autosomal dominant. Management: Regular skin checks for early detection of skin cancers and treatment of associated conditions. Periodontal disease related to genetics.