Chapter 2: Biochemistry (Part 2)

If you're enjoying this Crush Step 1 podcast, you can now get the content, along with the content of the Med Prep To Go Step 1 Questions podcast, add free in one bundle. Just go to MedPrepToGo.com and find our new subscription podcast called the Med Prep To Go Step 1 Bundle. Propel Fitness Water with Gatorade Electrolites, Zero Sugar, and Vitamins. Propel hydrates better than water to help you get the most out of your workout and get back to your best self. What propels you? Propel with Gatorade Electrolites. On any journey using Uber, it helps to know you're getting into the right car. Pin verification adds an extra step to make sure your ride is your ride. Before the trip begins, your app gives you a unique pin. Just tell it to your driver, and they'll enter it in their app before the ride can start. Hey, what's your pin? Mm-hmm. Two, five, three, eight. That way, you know you're in the right car taking the right trip, and your driver knows you're the right passenger. Make sure your ride is your ride with pin verification from Uber. One more way Uber is putting safety at every turn. Learn more on the Uber app. Have you heard that McDonald's spicy chicken McNuggets made with spicy tempura and a blend of aged cayenne are back? Remember to grab a few extra napkins. For a limited time at participating McDonald's. I'm Ted O'Connell, one of the authors of Crush Step One, the ultimate USMLE Step One review, along with my co-authors, Ryan Pettigo and Thomas Blair. I am also the Chief Content Officer for Inside the Boards. This is a Crush Step One podcast based on the second edition of our best-selling book. The goal is to provide you high yield and high quality audio content of the book to help you study on the go and reclaim some of the time in your day. This is Alec Ludwig narrating part two of the biochemistry chapter. Heem synthesis and metabolism. Heem is comprised of the tetra-pyrol ring, protoporferin Ix, with one coordinating ferrous, or iron 2 plus, iron ion in the center. Heem is found not only in Hemoglobin and myoglobin, but also in cytochromes, catalysts, and many other proteins. Heem is synthesized primarily in the liver, especially by cytochrome P450 and the bone marrow. The first reaction and the last three reactions occur in the mitochondria, whereas the rest of the reactions occur in the cytosol. Because reactions occur in the mitochondria, mature red blood cells cannot synthesize heme because of their lack of mitochondria. The steps in heme synthesis include the following. First, delta amino lebulinic acid, or ALA, is formed from glycine and succinyl CoA, in a reaction catalyzed by ALA synthase, and requiring pyrodoxyl phosphate as a coenzyme. This is the rate limiting step of heme synthesis. The paddock ALA synthase is inhibited by hemen, a heme molecule with oxidized iron 2 plus to iron 3 plus, that forms when porferin production is higher than its corresponding protein production. However, the rhithropoietic heme synthesis is instead controlled by a rhithropoietin and iron levels. When drugs that are metabolized by the cytochrome P450 system are metabolized, there is increased production of cytochrome P450 enzymes and a decrease in the heme concentration in the liver. This causes upregulation of ALA synthase production and activity. In the second step of heme synthesis, porfobillinogen is produced by ALA dehydrates, an enzyme that is inhibited by lead. Another enzyme, ferrokeletase, is also inhibited by lead. Thus, anemia and elevation in ALA are commonly seen in lead poisoning. Be sure to check out figured 2.15, which depicts the pathway of heme synthesis. Porfiorias are disorders of heme synthesis, leading to accumulation of heme precursors. The term porfioria means purple pigment, referring to the purple color of the urine of some patients. There are two kinds of porfiorias. Deficiencies in liver heme synthesis, called hepatic porfiorias, and deficiencies in bone marrow heme synthesis, called arithropoietic porfiorias. In some of these porfiorias, there is photosensitivity caused by accumulation of tetrapyrrole intermediates, which form superoxide free radicals that destroy cellular components upon exposure to ultraviolet light. Porfioria cutania tarda is the most common porfioria. It is caused by deficiency in uro porfiorinogen decarboxylase. Photosensitivity is caused by porfiorin accumulation. urine has a characteristic red brown color. hepatic porfiorias, such as acute intermittent porfioria, hereditary co-pro porfioria, and porfioria variegate, caused acute abdominal pain, psychiatric symptoms, and cardiovascular problems. Drugs that induce cytochrome P450 synthesis can precipitate attacks of hepatic porfioria, because increased cytochrome P450 synthesis reduces heme, increasing ALA synthesis, and thus increasing the accumulation of heme precursors. Arithropoietic porfiorias, such as congenital arithropoietic porfioria, and arithropoietic proto porfioria, present with photosensitivity, blisters, and urine that changes to a red brown color. Be sure to check out table 2.4 on page 30. It depicts inborn errors of porfiorin metabolism. Heme degradation occurs in the spleen by macrophages, and in the liver by hepatocytes. Within macrophages, hemoglobin and cytochromes are digested into heme, which is converted into beliveredin, a green pigment by heme oxygenates. Beliveredin is reduced, forming bilirubin, a yellow pigment. Because bilirubin is relatively insoluble in plasma, bilirubin is bound to albumin for transport in the blood to the liver. Upon arrival in hepatocytes in the liver, bilirubin becomes bilirubin hukurinide, or conjugated bilirubin. Using the enzyme bilirubin hukuronal transferase, an enzyme that is deficient in patients with cragler, nijar, and gilbert syndromes. The conjugated bilirubin is secreted into bile and transported to the intestine, where it is oxidized into stericobillin and excreted, the brown pigment in feces, converted into urobillin and excreted in urine. The yellow pigment in urine, or enters the enterohopatic urobillinogen cycle. Nucleic acid structure and function. Nucleic acid structure. Nucleic acids include DNA, or deoxyribonucleic acid, and RNA, ribonucleic acid. Nucleic acids are assembled from nucleotides, which are composed of a five carbon sugar, a nitrogenous base, and one to three phosphate groups. The sugar can be ribose in RNA, or deoxyribose in DNA. The nitrogen-containing base may be appearing adenosine or guanine, or a pyrimidine, cytosine, thymidine, or ursil. Thymine is specific for DNA, whereas ursil is specific for RNA. DNA has several structural forms. The B form is active DNA, whereas the Z form is inactive. Purine metabolism. Purine nucleotides are synthesized de novo, from several compounds, including CO2, glycine, glutamine, aspartate, and N10 formula tetrahedral folate. The synthesis of purines is an 11-step process. The first step is synthesis of PRPP, or 5-phosphorybosyl-1 pyrophosphate, from adenosine triphosphate, or ATP, and ribose-5-phosphate, a reaction catalyzed by PRPP synthetase. The second step is the regulated step of purine synthesis using the enzyme glutamine-phosphorybosyl-pyrophosphate amino transfers. The next nine steps leads to the synthesis of IMP, or Inozine-5 monophosphate, two of these steps require N10 formula tetrahedral folate. Several drugs target the purine synthesis pathway by inhibiting the formation of tetrahedral folate, or THF. Inhibition of purine synthesis leads to a lack of DNA synthesis, resulting in inhibition of cell growth and division. The next steps in appearing synthesis involved formation of adenosine monophosphate, or AMP, or guanosine monophosphate, or GMP, from IMP. Microphinolic acid, an immunosuppressive drug used to prevent organ transplant rejection, is an inhibitor of IMP dehydrogenase, the first reaction to convert IMP to GMP. This reduces the proliferation of T and V cells, which are dependent on the denover pathway for appearing synthesis, resulting in microphinolic acids and immunosuppressive effects. The final step in production of purines is synthesis of nucleoside diphosphates, from nucleoside monophosphates, using nucleoside monophosphate kinases. Cell phonomides are analogues of periamino-benzoic acid, or pebba, and competitively inhibit the synthesis of bolic acid by bacteria. This inhibits the synthesis of THF, which slows the purine synthesis pathway in microorganisms, leading to antibacterial effects. Humans do not synthesize bolic acid, but instead obtain it from the diet. So, so phonomides affect only bacteria appearing synthesis. Methotrexate and trimethroprim inhibit dihydrofolate reductase. The inhibition of dihydrofolate reductase inhibits growth of cancer cells, in the case of methotrexate, and bacterial growth for trimethroprim, a specific inhibitor of bacterial dihydrofolate reductase. Because these drugs inhibit synthesis of THF and slow the purine synthesis pathway. However, methotrexate has toxicity for all dividing cells, including cells in the bone marrow, skin, immune system, and gastrointestinal tract, leading to numerous drug side effects. Be sure to check out figure 2.16A on page 32. It shows the simplification of the purine synthesis pathway, and also check out figure 2.16B also on page 32. It depicts folate synthesis and inhibitors. Another pathway to obtain purines is the purine salvage pathway, in which purines from the diet or cellular breakdown can be recycled. Hyposanthine and guanine are converted to IMP and GMP respectively. By the enzyme, hyposanthine, guanine, phosphoribosil transferase, or HGPRT. Lesh nihan syndrome is an x-linked recessive disorder, in which there is a deficiency of HGPRT. These patients are unable to salvage guanine or hyposanthine using the purine salvage pathway. This leads to increased PRPP and an increase in denobo-pearing synthesis. This then leads to increased PRPP in hyperecemia. Patients with Lesh nihan syndrome present at an early age with neurologic features such as self-mutilation, spasticity, and cognitive defects. Orange uric acid crystals can be found in their diapers. Although there is no cure, treatment with allopyrinol can decrease the hyperecemia. But it does not alter the neurologic symptoms. Purines are degraded into uric acid, which is excreted in the urine. Zanthine oxidase converts hyposanthine to zanthine, and then converts zanthine to uric acid. Two diseases are closely associated with degradation of periods. Gout occurs when there are high levels of uric acid in the blood, or hyperecemia. Because of either overproduction or under-excretion of uric acid, monosodium uric crystals deposit in the joints, leading to inflammatory arthritis. Most patients with gout under-excrete uric acid. These patients are treated with uricosuric drugs, such as probenicid, or sulfan pyrazone, which help to increase the amount of uric acid that is excreted. Patients with gout that overproduce uric acid are treated with allopyrinol, an inhibitor of zanthine oxidase. This leads to an increase in hyposanthine and zanthine, which are more soluble than uric acid and do not form crystal deposits. For both kinds of patients, acute gout attacks are treated with anti-inflammatory drugs, including non-steroidal anti-inflammatory drugs, or NSAIDs. And Colchocene, Colchocene stops the polymerization of microtubules, which inhibits the migration of neutrophils into the inflamed area. Adenazine deaminase, or ADA, deficiency, can lead to a form of skid. The accumulation of adenosine inhibits ribonuclease reductives, preventing production of DNA, and thereby the proliferation of lymphocytes. Patients with the most severe form have deficiencies in T cells, B cells, and N-K cells. Pyrimidine synthesis. The first step in pyrimidine synthesis is the formation of carbomoral phosphate, or CAP, by carbomoral phosphate synthetase 2. This is the regulated step of pyrimidine synthesis. After several more steps, uredine 5 monophosphate, or UNP, is synthesized. UNP can be converted into pyrimidines, thymidine monophosphate, or TMP, also known as thymidylate, uredine triphosphate, or UTP, and cytidine triphosphate, or CTP. Deficiency of UNP synthase, which is a bifunctional enzyme, composed of both borotidine phosphate decarboxylase, and orotate phosphoribosyl transferase, causes orotic aciduria. Patients have severe anemia, poor growth, and orotate excreted in the urine. Treatment involves feeding synthetic uredine to supply the pyrimidine nucleotides that are needed for DNA and RNA synthesis. And get back to your best self. What propels you? Prepaul with gatorate electrolytes. "Hey, what's your pin?" "Mm-hmm, 2538." That way, you know you're in the right car taking the right trip, and your driver knows you're the right passenger. Make sure your ride is your ride, with pin verification from Uber. DNA replication. DNA replication begins at the replication fork, where helicases help to separate the strands of DNA. Topo isomerases act to remove supercoiled structures that are formed by this process. Several anti-cancer agents, such as etoposide, inhibit topo isomerase 2. Primease adds an RNA primer for DNA synthesis. DNA polymerases, or DNAP, synthesize DNA in the five prime to three prime direction. Two daughter strands are formed. One leading strand synthesized continuously in the five prime to three prime direction toward the replication fork, and one lagging strand synthesize discontinuously in the five prime to three prime direction away from the replication fork, using short DNA fragments called okazaki fragments. Be sure to check out figured 2.17 on page 33. It shows an illustration of DNA replication. DNA repair. DNA need repair because of environmental damage, such as ultraviolet or UV light, or chemicals, mistakes in DNA synthesis, or spontaneous loss of bases. Cells have three principal mechanisms to counteract single-stranded DNA damage. In DNA mismatch repair, or MMR, mismatches in daughter DNA strands, compared with the parent DNA are removed by an exonuclease and correctly filled in by DNA polymerase. Preredatory non-poliposis colorectal cancer, or HM-2, or HM-2, or HM-2, or HM-2. PCC is caused by defects in mismatch repair, most commonly in the MSH2G, and leads to an increased risk of colon cancer and other types of cancer. Nuclear Tide Excision Repair, or NER, is used to correct errors created by UV radiation damage. UV light can cause DNA damage by covalent joining of two thymids that are next to each other, creating a thymine dimer. In NER, UV-specific endonucleases cut one side of the double helix, and then DNA polymerases synthesize a new DNA strand. DNA polymerase has an exonuclease activity, which exercises the damage strand from 5 prime to 3 prime. Finally, DNA ligase joins the ends together. Zero-derma pigmentosum is an autosomal recessive disorder that results from defective nucleotide excision repair caused by a mutant UV-specific endonuclease. This leads to high rates of skin cancer after exposure to UV light, including melanoma, squamous cell carcinoma, and phasal cell carcinoma. In base excision repair, or VR, altered bases are recognized by DNA glycosolases, and cleaved from the DNA backbone, and several other enzymes assist in repair of the site. Other diseases such as ataxia, telangeptasia, and cone syndrome, and bloom syndrome, are also associated with defects in DNA repair. Carbohydrate, structure, and metabolism. Carbohydrate structure. Glucose oxidation provides much of the energy needed by cells in the fed state. Monosaccharides are classified as either aldoses, aldehydes, or ketosis, ketones. Although most sugars can exist as either D or L-form optical isomers, most human sugars are D-form. The general formula for monosaccharides is parenthesis CH2O parenthesis subscript x, with the number of carbons being key. Triose sugars have three carbons; tetros have four carbons; pentose or furanos have five carbons, such as ribose, fructose, and deoxyribose; hexose have six carbons, such as glucose, lactose, and fructose. Monosaccharides can link together through condensation reactions to form dysaccharides and oligosaccharides. The bond linking sugars is called a glycosidic bond, which either can be alpha or beta. Some important examples of dysaccharides are maltose is glucose plus glucose, lactose is glucose plus galactose, and sucrose is glucose plus fructose. Polysaccharides can be linear, such as amylose or branched, such as glycogen. Starch is the primary glucose storage molecule in plants. Starch can be broken down by humans using amylase. Starch has two components; amylose, or linear alpha-14 linkages, and amylopectin, branched alpha-14 linkages, and alpha-16 linkages. Glycogen is the main way that animals store glucose. The linkages are alpha, glycosidic, branched alpha-14, and alpha-16. Each glycogen has one reducing end, and many non-reducing ends. Glycogen is produced by the liver and muscle from excess glucose. Cellulose is an insoluble fiber, because it has beta-14 linkages, and humans only have enzymes that cleave alpha glycosidic bonds, such as those contained in starch. Glycosis involves the oxidation of glucose, and occurs in the cytosol of all cells. Glycosis can be either aerobic or anaerobic. In aerobic glycosis, or with oxygen, glucose is oxidized to pyruvate. The pyruvate and NADH, created in aerobic glycosis, can be used by the citric acid cycle, and the mitochondrial electron transport system, to generate 36-38 ATP molecules by oxidative phosphorylation. In anaerobic glycosis, or without oxygen, glucose is oxidized to lactate. Lactate dehydrogenase converts pyruvate to lactate, forming 2 ATP molecules per glucose molecule, and reoxidizing NADH to NAD+. Anaerobic glycosis occurs in anoxic tissues, red blood cells, and skeletal muscle during intense exercise. There are 9 steps in glycosis. 3 regulated enzymes catalyze irreversible reactions in glycosis, hexokinase, phosphofructokinase, and pyruvate kinase. The first step in glycosis is phosphorylation of glucose into glucose 6 phosphate, by either hexokinase or glucose kinase. Phosphorylation traps glucose inside cells, because phosphate is negatively charged, and charged compounds cannot easily cross cell membranes, and there is no specific transporter for glucose 6 phosphate. Hesokinase is found in the cytosol of most tissues, hexokinase has a low KM, or high affinity for glucose, ensuring that hexokinase is saturated at normal blood glucose concentrations. Hesokinase is not specific for glucose, and can catalyze the phosphorylation of many different hexoses. Hesokinase is also inhibited by glucose 6 phosphate, which prevents too much glycosis occurring, and cells accumulating too much glucose. Glucocinase is present in the liver, and beta cells of the pancreas. In contrast to hexokinase, glucose kinase has a high KM, or low affinity for glucose, meaning that glucose kinase is not saturated at normal blood glucose concentrations, but instead is able to act as a glucose sensor for the liver and beta cells to maintain glucose homeostasis. Glucocinase is highly specific for glucose. Glucocinase is inhibited by fructose 6 phosphate, which prevents glucose from being phosphorylated faster than it is metabolized. The rate limiting step for glycosis is the phosphorylation of fructose 6 phosphate by phosphofructokinase 1, or PFK1. Fructose 26bisphosphate strongly activates PFK1. Fructose 26bisphosphate is created by phosphofructokinase 2, or PFK2. A bi-functional enzyme that can either produce fructose 26bisphosphate using kinase activity, or produce fructose 6bisphosphate using phosphatase activity. After a meal, insulin levels increase and glucagon levels decrease. This causes an increase in fructose 26bisphosphate, activating PFK1, and increasing the rate of glycosis when glucose is plentiful. In contrast, in the fasting state, there is a decrease in fructose 26bisphosphate, leading to a decrease in the rate of glycosis. The final irreversible reaction of glycosis is formation of pyruvate from phosphoenopyrvate, which is catalyzed by pyruvate kinase. A mutation in pyruvate kinase causes hemolytic anemia. When pyruvate kinase is mutated, the ATP generated by anaerobic glycosis necessary for red blood cell function is not made, causing red blood cells to die prematurely and resulting in hemolytic anemia. Be sure to check out figure 2.18 on page 35. It depicts the full pathway of glycosis. Gluconeogenesis Gluconeogenesis, the process by which glucose is synthesized, occurs primarily in the liver and kidneys. The carbon sources of the synthesis of glucose is from small precursors, including pyruvate, lactate, glycerol, and glucogenic amino acids. The glucose released from gluconeogenesis is released into the bloodstream. Gluconeogenesis composed of the reversible reactions of a chord. glycolysis, as well as several reactions specific to gluconeogenesis that bypass the irreversible reactions of glycolysis. 1. Conversion of pyruvate to phosphoenopyrvate, which bypasses pyruvate kinase. 2. Conversion of fructose 1/6bisphosphate to fructose 6phosphate, which bypasses phosphofructokinase, 2. Conversion of glucosixphosphate to glucose, which bypasses hexokinase. To convert pyruvate to phosphoenopyrvate, pyruvate is first carboxylated to oxaloacetate, by pyruvate carboxylase. In a second reaction, oxaloacetate is converted to phosphoenopyrvate by phosphoenopyrvate carboxy kinase. Fructose 1/6bisphosphate is converted to fructose 6phosphate by fructose 1/6bisphosphatase. Fructose 1/6bisphosphatase is inhibited by fructose 2/6bisphosphate, a molecule that activates PFK1 in glycolysis. This ensures that both pathways are not active at the same time. Glucosixphosphate is converted to glucose by glucosixphosphatase. This enzyme is also essential for the last step of glycolysis, and a deficiency of glucosix phosphatase leads to type 1a glycogen storage disease or Von Gurkey disease. There is hypoglycemia in this disorder because the patients are unable to produce glucose by glycogenolysis or gluconeogenesis. Glycogen synthesis and degradation, glycogen, a polysaccharide, is the way the body stores glucose in a form that can be rapidly mobilized to maintain glucose homeostasis and to serve as fuel for muscles. Glycogen is stored primarily in the liver and muscle tissue, but small amounts are present in most cells. Glycogenesis is the production of glycogen and occurs in the cytosol. The substrate for glycogenesis is Euridine Daphosphate or UDP glucose. Glycogen synthase adds to the non-reducing end of chains in alpha-14 linkages. Branches with alpha-16 linkages are created by a branching enzyme, Amelow-Alpha-14-16 transglucositis. Glycogenesis is stimulated by insulin and inhibited by glucogone and epinephrine. Glycogenolysis is the breakdown of glycogen and occurs in the cytosol. First, glycogen phosphorylase cleaves alpha-14 glycosidic bonds between individual glycosyl residues, non-reducing ends, forming glucose-1 phosphate. Next, glucose-1 phosphate is converted to glucose-6 phosphate by phospho-glucomutase. Glucose-6 phosphatase can then convert the glucose-6 phosphate into glucose. The D branching enzyme releases free glucose from alpha-16 bonds at the branching points. Glycogen stimulates glycogenolysis while insulin inhibits glycogenolysis. Glycogen storage diseases. Several inherited deficiencies of glycogen metabolism lead to glycogen storage diseases. Type 1 or Fongerkey disease has a deficiency of glucose-6 phosphatase, which causes an increased amount of glycogen in the cells with normal structure. It is acquired by autosomal recessive inheritance, and notable clinical features are hepatomegaly and hypoglycemia. Type 2 or Pompei disease has a deficiency of alpha-14 glucose-6 which causes an increased amount of glycogen in the cells with normal structure. It is acquired by autosomal recessive inheritance, and notable clinical features are cardiac and respiratory failure and early death. Type 3 or Cori disease has a deficiency of deep branching enzyme, which causes an increased amount of glycogen in the cells with short branches. It is acquired by autosomal recessive inheritance, and notable clinical features are similar to Vongerkey disease, but with milder symptoms. Type 4 or Anderson disease has a deficiency of branching enzyme, which causes an increased amount of glycogen in the cells with long branches. It is acquired by autosomal recessive inheritance, and notable clinical features are liver cirrhosis and early death. Type 5 or Macartle disease has a deficiency of phosphorylase, which causes a small increase in the amount of glycogen in the cells with normal structure. It is acquired by autosomal recessive inheritance, and notable clinical features are muscle cramps with exercise. Type 6 or Herz disease has a deficiency of phosphorylase, which causes an increased amount of glycogen in the cells. Make sure to check out Table 2.5 on page 37 to depicts all the glycogen storage diseases, types 1 through 6 that were previously just discussed. Metabolism of sugars Lactase metabolizes lactose to glucose and galactose. Galacto kinase converts galactose to galactose 1 phosphate. In several reactions, galactose 1 phosphate becomes glucose 1 phosphate. Lactase deficiency leads to milk intolerance and causes bloating and diarrhea after ingestion of lactose-containing products. Galacto kinase deficiency causes a mild galactosemia leading to galactotol accumulation and cataracts formation. Galactose 1 phosphate, Eurodil transferase deficiency, causes severe galactosemia, resulting in failure to thrive, mental retardation, liver dysfunction, cataracts, and susceptibility to infection. Sue grace converts sucrose to glucose and fructose. Note that hexokinase can convert fructose to fructose 6 phosphate by phosphorylation in the liver and kidney. Fructokinase deficiency leads to essential fructoseuria, which is a benign disorder. However, fructose 1 phosphate aldolase deficiency leads to hereditary fructose intolerance. This causes severe hypoglycemia after ingesting fructose or sucrose. Be sure to check out figure 2.19 on page 37, it depicts the pathway of the breakdown of sucrose, pentose phosphate pathway. The pentose phosphate pathway can be used either for glycolysis or for oxidation of glucose. The oxidative processes, which are irreversible, generate NADPH, needed for pathways such as the synthesis of fatty acids and cholesterol. The non oxidative processes, which are reversible, rearrange sugars so that they can enter glycolytic pathways. Additionally, ribose 5 phosphate can be formed by the pentose phosphate pathways and used for synthesis of nucleotides. G6PD is an enzyme of the pentose phosphate pathway that provides a key regulatory role. Patients with G6PD deficiency, an excellent recessive disorder, are unable to effectively produce NADPH through the pentose phosphate pathway. This prevents cells from maintaining reduced glutathione, which results in increased oxidative stress on cells, particularly erythrocytes, leading to hemolytic anemia. Some patients with G6PD deficiency only develop anemia when they experience oxidative stress, such as by taking accident drugs, such as sulfamethoxysol, and pramachin, eating phababines, or infection. The TCA cycle, the tri-carboxylic acid, or TCA cycle, also known as the citric acid cycle, or CREB cycle, occurs in the mitochondria. red blood cells do not have mitochondria. The pyruvate produced from glycolysis becomes acetyl-Coenzyme A or acetyl-CoA through the enzyme pyruvate dehydrogenase. Fatty acids can also yield acetyl-CoA by beta oxidation. The TCA cycle begins when oxaloacetate condenses with acetyl-CoA to form citrate. For one pass through the TCA cycle, oxaloacetate is regenerated. Two moles of CO2 are released, one guanosine triphosphate or GTP is produced, and 11 moles of ATP are produced by oxidative phosphorylation. Be sure to check out figure 2.20 on page 39. It depicts an illustration of the entire tri-carboxylic acid cycle. Electron transport and oxidative phosphorylation. The chemiasmonic hypothesis describes the coupling of the electron transport chain to the synthesis of ATP through flow of electrons. As electrons are pumped through the complexes of the electron transport system, hydrogen ions are pumped into the intermembrane space of mitochondria. This forms a proton-motiv force from a pH and electrical potential gradient across the mitochondrial membrane. Hydrogen ions passing through ATP synthase down their concentration gradient drive the formation of ATP through ATP synthase. Uncoupling agents carry hydrogen ions across the inner mitochondrial membrane without transport through ATP synthase. This on couples flow of electrons and ATP synthase. This leads to energy dissipated as heat instead of synthesis of ATP. Uncoupling proteins play an important role in animals that hibernate, where stored energy generates heat. In newborn mammals, brown fat has thermogenin, which is an uncoupling protein. This allows energy to dissipate as heat. However, in humans, uncoupling agents such as two-four-dynitrophenol taken in the past for weight reduction are poisonous. Several compounds inhibit flow of electrons through the electron transport chain, including cyanide, carbon monoxide, hydrogen sulfide, and ammo-barbitol, lipid structure and metabolism, lipid structure. Fatty acids are the building blocks of lipids. Fatty acids are oxidized in the fasting state to provide energy to cells. Two fatty acids must be supplied in the diet, linoleic and alpha linoleic acid. Fatty acids are made up of an unbranched hydrocarbon chain with a terminal carboxyl group. Most fatty acids have an even number of carbon atoms and 16 to 20 total carbons. Short chain fatty acids have two to four carbons and medium-chain fatty acids have six to ten carbons. They can be directly absorbed in the small intestine. They can also diffuse into the mitochondrial matrix and be oxidized directly. Long-chain fatty acids have 12 or more carbons. They are in triasyl glycerols or fat. To move from the cytosol into the mitochondria, they require the carnitine shuttle. Unsaturated fatty acids have at least one double bond, most commonly cis rather than trans configuration. Trans fatty acids are formed during the production of hydrogenated vegetable oils and have been associated with an increase in atherosclerosis. Triasyl glycerols are formed by estrification of fatty acids with glycerol. These have nine kilocalories per gram and are stored in adipose tissue. Stereoids are a kind of lipid with a four-membered ring structure and a hydroxyl or keto group on the third carbon. There are five major groups of steroids. One cholesterol are 27 carbons, the most abundant steroid in humans and important in cellular membrane fluidity. Precursor of steroid hormones skin-derived vitamin D and bile acids. Two, bile acids, 24 carbons, includes colic acid. Three, progesterone, and adrenocortical steroids, 21 carbons. Four, androgens, 19 carbons. Five, estrogens, 18 carbons, derived from aromatization of androgens. Cholesterol synthesis is regulated by three hydroxy, three methyl gluturil or HMG coA reductase, and a key intermediate in cholesterol synthesis is HMG coA. Stattons are HMG coA reductase inhibitors. Phospholipids are a major component of cell membranes and are created from phosphatitic acid which is diacylglycerol plus a phosphate group on C3. Phospholipids are cleaved by phospholipases. Phospholipase A1 and A2 remove fatty acyl groups. Phospholipase A2 in cell membranes is activated by cytosolic calcium 2 plus, which causes damage to cell membranes when tissues undergo hypoxia. Phospholipase A2 is inactivated by corticosteroids, reducing the release of a racodonic acid. Phospholipase C frees its component compounds, diacylglycerol, and anositol triphosphate, which are important in intracellular signaling. Phospholipase D makes phosphatitic acid from phospholipids. Long sirfactin is important in decreasing the surface tension in alveoli. It is particularly rich in phosphatideal colines. Insufficient production of long sirfactin by premature infants leads to respiratory distress syndrome, which is characterized by poor gas exchange and partial lung collapse. Be sure to check out Figure 2.21 on page 40. It shows the structure of A fatty acids, B2 monol acyl glycerol, and C triacylglycerol. Phospholipids and Phospholipids storage diseases. Phospholipids are derived from ceramide, a molecule that is formed by coupling of fatty acid and sphingosine, which is sphingosine plus fatty acids equals ceramide. Sphingolipids are essential components of membranes throughout the body and are particularly abundant in nervous tissue, especially in the white matter of the CNS. Lysosomal enzymes degrade sphingolipids to sphingosine using several hydrolytic reactions. Sphingolipidosis are a group of hereditary Lysosomal enzyme deficiency diseases in which one of these hydrolytic enzymes in the degradative pathway is deficient. Deficiencies of sphingolipid degrading enzymes in lysosomes, remember lysosomes contain hydrolytic enzymes, lead to the accumulation of the substrate in lysosomes, and thus to lysosomal storage diseases. In most of these diseases, neurologic deterioration and early death occur. Also note that fabric disease is ex-linked recessive rather than autosomal recessive. Some important genetic disorders of sphingolipid degradation are as follows. Taysac's disease has a deficiency of hexos and mendedase A, which causes an accumulation of GM2 ganglia sides. It is acquired by autosomal recessive inheritance, and notable clinical features are developmental regression, muscle weakness, blindness, cherry red macular spot, deafness, no hepatosplenomegaly, and death. Goucher disease has a deficiency of beta glucosides, which causes an accumulation of glucocerebrosides. It is acquired by autosomal recessive inheritance, and notable clinical features are joint and limb pain, hepatosplenomegaly, macrophages appearing like crinkled paper. Neiman-picked disease has a deficiency of sphingo myelonase, which causes an accumulation of sphingo myelon. It is acquired by autosomal recessive inheritance, and notable clinical features are failure to thrive, hepato splenomegaly, cherry red spot, developmental regression, and macrophages appearing bubbly. Fabury disease has a deficiency of alpha galactosides, which causes an accumulation of ceramide-trihexocides. It is acquired by ex-link recessive inheritance, and notable clinical features are cataracts, kidney and heart failure, and parasthesias. Crab disease has a deficiency of beta galactosides, which causes an accumulation of galacto cerebrocides. It is acquired by autosomal recessive inheritance, and notable clinical features are progressive psychomotor retardation, glow-boid bodies in the brain, white matter, and death. Metacromatic leukodystrophy has a deficiency of aero-sulfatase A, which causes an accumulation of sulfatides. It is acquired by autosomal recessive inheritance, and notable clinical features are mental retardation and peripheral neuropathy. Be sure to check out table 2.6 on page 41. It describes the genetic disorders of singolipid degradation that were just previously described. Icosenoids. Icosenoids are important short range, or autocrine and paracrine, signaling molecules that are formed by oxidation of 20 carbon essential fatty acids by phospholipase A2, including icosipentinoic acid, anomega-3 fatty acid, and arachidonic acid, anomega-6 fatty acid, synthesized from the essential fatty acid, linoleic acid. There are four subtytes of icosenoids, leukotrienes, or LTs, and three types of prostenoids. Prosteglandins, PG, Prostocyclins, PGI, and thrombocanes, TX. LTs are non-cyclic. They are synthesized by hydroxylation of arachidonic acid by lipboxogenases. leukotriene B4, or LTB4, is an important chemotactic agent for neutrophils, and also increases neutrophil adhesion. LTC4, LTD4, and LTE4 are known as slow reacting substance of anaphylaxis, an increased bronchoconstriction, vasoconstriction, and vascular permeability. LT inhibitors are used for treatment of asthma, and include xylutin, an inhibitor of lipoxygenase, and zyfarolucast, and Montelucast, which are leukotriene receptor antagonists. PGs are created when cyclooxygenase acts on arachidonic acid. Prosteglandin H2, or PGH2, is the first stable prosteglandin produced in this pathway. PGs produce inflammation, inhibit or stimulate muscle contraction, and promote vasodilation or vasoconstriction, depending on the vascular bed. PG-E2 interacts with several different prosteglandin receptors, which are G-protein-coupled receptors, and leads to vasodilation, inflammation, and an increase in gastric mucus secretion. PG-E2 is known as dinoprostone, and is used in labor to prepare the cervix for induction of labor, but also has been demonstrated to sustain fetal, ductus, arteriosus, patency. PGF2-alpha stimulates uterine contractions, and also increases vasoconstriction. Analogs of PGF2-alpha include dinoprost, latana-prost, bematoprost, and trava-prost. They are used in medicine to induce labor and as a board of patients. Aspirin is an irreversible cyclooxygenase inhibitor. Prostegland, or PG-E2, is an effective vasodilator and bronchodilator, and inhibits platelet activation. Synthetic prostocycline analogs, such as iloprost and cystoprost, are used as vasodilators in severe renaud disease, and in pulmonary hypertension. As a drug, PG-E2 is known as epoprostinol. PG-E2 is produced in endothelial cells from PG-H2. Prostocycline is in cardiovascular homeostasis with thromboxane A2, or TX-A2. TX-A2 is produced in platelets from PG-H2 by thromboxane synthase. TX-A2 promotes contraction of arterials and aggregation of platelets. Diperimidol inhibits thromboxane synthase, aspirin, and other NSADS acetylate and inhibit cyclooxygenase, leading to reduced synthesis of prosteglandins, or an anti-inflammatory effect, and reduced synthesis of thromboxane A2, or an anti-thrombotic effect caused by reduced platelet activation. By inhibiting phospholipase A2, corticosteroids inhibit the production of all icosinoids. Fatty acid, oxidation, and synthesis. Fatty acids are oxidized to CO2 and H2O in the mitochondrial matrix. Long-chain fatty acids must be shuttled into the mitochondrial matrix by the carnitine transport system, because they cannot cross the mitochondrial intermembrane alone. Medium-chain fatty acids are able to pass directly through the mitochondrial membrane. The oxidation of fatty acids occurs by the beta-oxidation system of the mitochondria, where each cycle produces 17 ATP molecules using the electron transport system and citric acid cycle. Fatty acids are synthesized from acetylcoA and malonylcoA by fatty acid synthase. Seven reaction cycles yield palmitate and fatty acid synthase. Palmitate acts as the precursor to other fatty acids. Longer fatty acids are synthesized by chain lengthening systems, and unsaturated fatty acids are synthesized by a desaturating system. However, the desaturating enzymes are only able to desaturate double bonds greater than 10 carbons from the C-terminus. Therefore, linoleic acid and linoleic acid are essential fatty acids. Be sure to check out figure 2.22 on page 42, which depicts the entire pathway of fatty acid synthesis. With that, we wrap up today's episode of the Crush Step 1 podcast. A big thank you to Elsevere Incorporated, the publishing company behind Crush Step 1, as well as all of my other books, for allowing us to put out this book in podcast format. Thank you for joining us, and please check out our other chapters. 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