Chapter 2: Biochemistry (Part 1)

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Hey everyone, Chris here from Med Prep to Go, and I wanted to let you know about our premium Step 2 Bundle podcast, which gives you all of the Step 2 secrets and their Step 2 Questions podcast combined and add free. You'll also get early access to all of our Step 2 Questions episodes before they're released public. The Bundle podcast is available now, and you can save over 40% with an annual plan. Details at MedPrep2Go.com. Hey everyone, Chris here from Med Prep2Go, and I wanted to let you know about our premium Step 1 Bundle podcast, which gives you all of Crush Step 1 and our Step 1 Question podcast combined and add free. You'll also get early access to new content as it becomes available. Upgrade your studying now and learn more at MedPrep2Go.com. I'm Ted O'Connell, one of the authors of Crush Step 1, the ultimate USMLE Step 1 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 1 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. I'm a recent graduate from Michigan State University College of osteopathic medicine, who will be starting residency at the Sutter Santa Rosa Family Medicine Residency Program in July. I will be narrating the biochemistry chapter of Crush Step 1, second edition. Protein structure and function. Amino acid structure. Amino acids are the building blocks of proteins. Amino acids are comprised of an alpha amino group and an alpha-carboxyl group with different characteristic side chains. 20 amino acids are naturally incorporated into polypeptides. Nine of these amino acids are essential, cannot be synthesized by humans, and must be obtained in the diet. These essential amino acids include phenylalanine, vaniline, three anine, triptophane, isolucine, methyonine, histidine, lucine, and lysine. In children, an additional three amino acids are essential, arginine, tyrazine, and cystine. In adults, the remaining 11 amino acids can be synthesized. The nature of the amino acid side chain is critical to how proteins interact with their environment, acidic, basic, and uncharged polar side chains tend to be found on the exterior of soluble proteins and on the interior of proteins found within membranes. Conversely, amino acids with non-polar side chains are located in the interior of proteins that exist in aqueous environments and on the exterior of portions in lipid environments. Aline is an important substrate for gluconeogenesis. Isolucine, valine, and lucine are branched chain amino acids that are increased in maple syrup urine disease. Methionine is a precursor of homocysteine, a product associated with atherosclerosis. Increased levels of homocysteine are seen in patients with classic homocysteine area, with a deficiency in cystethyning beta-synthes. These patients have early onset vascular disease. Fennel-aline accumulates in Fennel-Kitine area, PKU. Triptivine is a precursor of serotonin, niacin, and melatonin. Arginine and histidine stimulate growth hormone and insulin. Arginine is a precursor of nitric oxide. Glutamine is the most common amino acid and is an important nitrogen donor in the synthesis of purines and perimities. Cisteen forms disulfide bonds and is sensitive to oxidation state. Proline is different from other amino acids because its side chain forms a five-membered ring. Proline is often found in collagen and its unique side chain is used to interrupt alpha helices in globular proteins. The PKA, or the negative log of the acid dissociation constant, KAA, is a measure of the strength of an acid insolution. The PKA of amino acid side chains give insight into the pH characteristics of proteins and stability. Histidine is unique in that its side group, might as all, has a PKA of 6. This means the histidine has a positive charge at pH of 7. And a physiologic pH, small shifts in pH change the charge of histidine, and the side group acts as a buffer. A spartic acid and glutamic acid have a negative charge at a pH of 7. Albumin is a strong binding protein for positively charged molecules, in part because of its high content of these acidic amino acids. The isoelectric point, or PI, is the pH value at which an amino acid or any other molecule has a net zero electrical charge. Amino acids are zwinor ions, with positive and negative charges. When pH is greater than PI, the net charge on the molecule is negative. When pH is less than PI, the net charge of the molecule is positive. At physiologic pH, lysine, barginine, and histidine have a positive charge, whereas aspartate and glutamate have a negative charge. Proteins can be separated based on their PI using isoelectric focusing on a polyacrylamide gel, which separates proteins using a pH gradient. This is the first step in two-dimensional gel electrophoresis. Make sure to take a look at figure 2.1 on page 16. It shows the 20 naturally occurring amino acids, their structure, their 1 and 3-letter representations, as well as the class of amino acids. Protein structure The primary structure of a protein is the linear sequence of amino acids. PepTide bonds are formed between the alpha-carboxyl group and the alpha amino group, creating a covalent amide linkage. Make sure to take a look at figure 2.2 on page 17. It shows protein primary structure. The secondary structure of proteins involves the arrangements of the amino acids located near each other in the amino acid sequence. Important secondary structure components include alpha helices and beta sheets. Alpha helices are the most common kind of polypeptide helis. Extensive hydrogen bonding occurs between the peptide bonding of carbonyl, oxygen, and amide hydrogen. Each alpha helical turn contains 3.6 amino acids. Therefore, amino acids that are spaced 3-4 amino acids apart in the primary structure are quite close together in an alpha helis. Proline disrupts alpha helices because its 5-membered ring structure forms kinks in the chain. Beta sheets or beta pleated sheets occur when 2 or more polypeptide chains known as beta strands are arranged by hydrogen bonding in parallel or antiparallel to each other. Bonds between polypeptide backbone of separate polypeptide chains are known as interchained bonds. Globular proteins tend to have beta sheets with a right-handed curl or twist, which form their core. Silk is a packed beta sheet. Proteins that bind to DNA also have important secondary structure motifs. For example, the DNA binding zinc finger motif is found in many transcription factors. The tertiary structure of proteins includes the three-dimensional shape of the folded protein chain. Several different kinds of interactions stabilize tertiary structures. Dysulfide bonds are covalently formed from the sulpa-hydro group of two cysteine residues. Dysulfide bonds are important in proteins that are secreted from the cell, such as immunoglobulins. Ionic interactions include negatively charged cy groups interacting with positively charged groups. Hydrophobic interactions force amino acids with non-polar side chains into the interior of polypeptide molecules, where they are able to associate with other hydrophobic residues. Amino-acids with polar side chains tend to be located on the surface of a protein and contact the polar solvent to be the most energetically favorable. Hydrogen bonds can form between amino acid side chains that have oxygen or nitrogen-bound hydrogen, such as serine or thoranine. This can help to improve the solubility of proteins in aqueous environments. The quattenary structure is the arrangement of polypeptide subunits in a protein structure that has more than one polypeptide chain. These subunits are usually held together by non-covalent interactions. Proteins fold in a very short timeline, milliseconds to microseconds, where the translation of protein from messenger RNA or mRNA progresses at a much slower rate, at about 5 to 20 amino acids per second. Chaperone proteins, such as the heat shock proteins, are critical in keeping some proteins properly folded. Proteins can be denatured by heat, solvents, strong acids or bases, and detergents. Some proteins can also misfold, and deposition of these misfolded proteins is associated with several diseases. Amoledoses are diseases in which an altered protein accumulates. In some amoledoses, insoluble, fibrillar proteins aggregate in a form that resembles beta sheets. In Alzheimer's disease, plaques form that contain amyloid beta, which is hypothesized to be neurotoxic. These amyloid beta peptides aggregate forming amyloid in brain tissue and in blood vessels. Alzheimer's disease is also defined by an accumulation of hypophosphorylated tau proteins known as neurofibreillary tangles. Prion diseases are caused by the Prion protein, an infectious protein that causes normal proteins to change structure and form insoluble aggregates of fibrils. Prion diseases include transmissible, spongiform and cephalopathy such as Kurtzfeld-Yakob disease in humans, Skrapy in sheep, and Bolvine spongiform and cephalopathy in cattle, also known as mad cow disease. It has been shown that many alpha helices present in non-infectious Prion proteins are replaced by beta sheets in the infectious form. This makes the protein highly resistant to proteolytic degradation. Hines bodies are formed when red blood cells undergo oxidative stress, whereby hemoglobin is denatured to form aggregates on the membrane of red blood cells. This occurs in conditions such as glucose-6-phosphate dehydrogenase deficiency, dalsimias, and exposure to oxidative compounds, oxygen-vining proteins, hemoglobin and myoglobin. Hemoglobin A, the most common hemoglobin in adults, is composed of two alpha-globin subunits and two beta-globin subunits. Each globin protein subunit is composed of an alpha or beta protein chain plus a hem group. Hem in turn is composed of an iron 2 plus held in a portal porphrine Ix ring. Hemoglobin has two primary forms. Hemoglobin that is desaturated with oxygen is deoxyhemoglobin, or T, the tense form, which has a low oxygen affinity and a lower degree of freedom. Hemoglobin that is saturated with oxygen is oxyhemoglobin, R, or relaxed form, which has a high oxygen affinity and a higher degree of freedom. A single hemoglobin molecule combine up to four oxygen molecules. The four globin subunits work cooperatively in hemoglobin in which the binding of oxygen to one subunit of the tetramer increases the affinity of the other subunits for oxygen. The first oxygen binds with low affinity, but this leads to a transition from T to R form. The second through fourth oxygen molecule is binding with increasing affinity, which leads to a sigmoidal oxygen binding or oxygen saturation curve for hemoglobin. Be sure to look at figure 2.4 on page 19. It shows the comparison of oxygen binding curves for hemoglobin and mild globin. Deoxyhemoglobin, or T form, preferentially binds hydrogen ion, 2, 3 bisphosphoglycerate, or 2, 3 B, P, G, and CO2. This leads to stabilization of the T state, decreased affinity for oxygen and a right-word shift in the oxygen saturation curve. Exercise and an increase in temperature can also cause a right-word shift. Conversely, a left-word shift in oxygen saturation curve occurs in the presence of a decrease in CO2, alkylosis, or a high pH, or low hydrogen ion concentration, and a decrease in 2, 3 B, P, G. Myoglobin is a single polypeptide chain with a single hemoglobin. Myoglobin is present in heart and skeletal muscle, and acts as an oxygen carrier and location for storage of oxygen. Myoglobin can only bind to one oxygen molecule, therefore the binding curve is hyperbolic rather than sigmoidal because the binding of O2 is not cooperative. Be sure to see this on figure 2.4 on page 19. Carbon monoxide, or CO, binds to hemoglobin to form carboxyhemoglobin, which has a high affinity for CO and displaces O2. This leads to stabilization of the R state, a left-word shift of the oxygen saturation curve and oxygen saturation curve for hemoglobin that resembles the curve for myoglobin. Hey everyone, Chris here from MedPrep2Go, and I wanted to ask you to please follow us on social. There may be links in the show notes, or you can find us at MedPrep2Go on Facebook, Instagram, LinkedIn, and now YouTube. We would greatly appreciate it as we try to spread the word about MedPrep2Go and keep medical education accessible and affordable. Do you need a break from studying? Check out the Dr. Raj podcast where he discusses topics such as wine with Jesse Katz, sarcoidosis with Bob Sagitt, saving the bees with Sydney S.L., and so much more. The podcast also features guest host Becca Spar, who focuses on leadership and connection, as well as Dr. Michelle Kulaii and her everyday room segment, where she talks to patients to share their stories and the challenges that come with different conditions. Just search for the Dr. Raj podcast wherever you're listening now and tune in for a variety of great guests and topics. Figure 2.4 compares the oxygen binding curves for hemoglobin and myoglobin. Myoglobin has a lower P50 than hemoglobin, meaning that it has a greater affinity for oxygen. This ensures that oxygen is bound to myoglobin in all cases except hypoxia. Chemoglobin apathes are a group of genetic disorders caused by abnormal hemoglobin structure or insufficient synthesis of normal hemoglobin. Sickle cell disease or hemoglobin S disease is a homozygous recessive genetic disorder that results from production of hemoglobin with an altered amino acid sequence caused by a single point mutation in the beta-globin gene. The mutation is a glutamate to valine mutation at position 6 in the beta-globin chain. During electrophoresis at a basic pH, hemoglobin S migrates more slowly for the anode or positive electrode than does hemoglobin A. As a result of the absence of the negatively charged glutamate residues in the two beta-globin chains which makes hemoglobin S less negative. The mutant beta-globin chain is designated beta S and the resulting hemoglobin alpha 2 beta 2 S is hemoglobin S. The alpha-globin chains are normal. This amino acid substitution forms a protrusion on the beta-globin that polymerizes deoxygenated hemoglobin S into fibers. The resulting sickle erythrocytes include blood flow in the capillaries causing [BLANK_AUDIO] microinfartions leading to tissue, anoxia, and severe pain. An infant does not begin to show symptoms of the disease until sufficient hemoglobin F has been replaced by hemoglobin S so that the cycling can occur. Sicling is increased by anything that increases the proportion of hemoglobin S in the deoxygenated state such as decreased O2 tension, increased PCO2, decreased pH, dehydration, and increased concentration of 2, 3 BPG in arithrocytes. Hydroxyurea is used to treat sickle cell disease because it increases circulating levels of hemoglobin F, which decreases red blood cell cycling. Sicle cell disease is tested for it birth to allow prophylactic antibiotic therapy to begin soon after because these children are at risk for sepsis. Hemoglobin C disease results from production of hemoglobin with an altered amino acid sequence as a result of a glutamate to lysine substitution at position 6 in the beta-globin gene. The substitution of a positively charged amino acid or a negatively charged amino acid causes hemoglobin C to move more slowly toward an anode than hemoglobin A or hemoglobin S does. Homosigis patients have a mild chronic hemolytic immediately. Hemoglobin SC disease occurs when some beta-globin genes have the sickle cell mutation, whereas others have the mutation found in hemoglobin C disease. These patients are compound heterozygurates because both of their beta-globin genes are abnormal but are different from each other. Effective individuals have fewer vaso-accusive events than those with sickle cell disease, but their course is more serious than those with hemoglobin C disease. Velocimus are caused by decreased production of normal hemoglobin as a result of defective synthesis of either the alpha or the beta-globin chain. In beta-thousyminus, synthesis of beta-globin chains is decreased or absent, but the alpha-globin chain synthesis is normal. Other forms of hemoglobin may be present in elevated amounts, including hemoglobin F or alpha-2 gamma-2 in beta-thousyminus and hemoglobin BART gamma-4 in alpha-thousyminus. Because there are only two copies of the beta-globin gene, individuals have either beta-thousyminiotrate or minor or beta-thousyminiot major or chuleonemia. Because beta-globin is not expressed into late ingestation, symptoms of beta-thousymini appear only after birth. Alpha-thousyminus occur when alpha-globin chains are decreased or absent. There are four copies of the alpha-globin gene, so there are several possible levels of deficiency. If one copy of the alpha-globin is absent or defective, the person is a silent carrier. Two defective genes leads to alpha-thousyminiotrate. Many defective genes lead to hemoglobin H disease. If all four alpha-globin genes are defective, hydrops fetalis and fetal death result, because alpha-globin chains are required for the synthesis of hemoglobin F. Be sure to check out figure 2.5 on page 20. It shows hemoglobin apathy. The pattern of hemoglobin A2, S, F and A, the type of anemia represented by the hemoglobin apathy and the atirpretation and discussion of these results. Fibrous proteins. Collagen is the most abundant protein in humans and is found primarily in connected tissue and muscle. Collagen is composed of a triple helix and three alpha chains held together by hydrogen bonds. There are more than 20 types of collagen. Collagen type 1 is the most common. Collagen has a large amount of proline and glycine residues. Proline helps in the formation of the alpha chain and glycine is found in every third amino acid. The sequence is glycine xy, where x is often proline and y is often hydroxyproline or hydroxy lysine. The biosynthesis of collagen occurs as follows. 1. It begins with mRNA transcription in the nucleus of a fibroblast or related cell. 2. MRNA is translated into pre-pro collagen on the rough endoplasmic reticulum or RER and these peptide chains are directed into the lumen of the RER and become pro-alpha chains. 3. Proline and lysine residues are next hydroxylated by prolyl hydroxylase and lysyl hydroxylase. 4. Some hydroxylycine residues are glycocylated with glucose and galactose. 5. Pro alpha chains form pro collagen which has essential triple helix with N and C terminal pro-peptide extensions. These prevent premature assembly of collagen within the endoplasmic reticulum. 6. Pro collagen is transported to the Golgi apparatus where it is released into the extracellular space. 7. After release of pro collagen, peptidases remove the terminal pro-peptides forming tropo collagen. 8. Tropo collagen then spontaneously assembles into collagen fibros. The collagen fibres are cross-linked by lysyl oxidase which oxidatively diaminates lysyl and hydroxylycine residues in collagen forming covalent cross-linked mature collagen fibros. Be sure to check out figure 2.6 which shows an illustration of collagen synthesis and assembler. The hydroxylation reaction requires both oxygen and the reducing agent vitamin C or scorbic acid, but the hydroxylating enzymes polo hydroxylase and lysyl hydroxylase to function. Vitamin C deficiency leads to a lack of polo and lysyl hydroxylation, making collagen fibres unable to be cross-linked which decreases the tensile strength of the assembled collagen fibre. This is called scurvy. Because of the weak collagen structure, patients often have bruises, corkscrew hairs, and perifilicular hemorrhage caused by capillary fragility. Copper is also a cofactor or lysyl oxidase. Elears Danlos syndrome, or EDS, is a connected tissue disorder caused by defects in collagen synthesis. EDS arises from lysyl hydroxylase deficiency, pro collagen peptidase deficiency, or mutations in collagen amino acid sequences, most importantly collagen type 3. Skin hyperextensibility and joint hypermobility are seen in patients with EDS. osteogenesis and perfective, or OI, also known as brittle bone disease, is a genetic disorder caused by defects in connected tissue, usually type 1 collagen, such as decreased production of collagen alpha chains, linked to bones that are prone to bend and fracture. OI is an autosomal dominant disorder, but arises sporadically in one third of cases. Type 1 OI is the most common form of OI, and is known as osteogenesis and perfective tarda. Blued typhoid, with type 1 OI, have bones that fracture easily, early hearing loss, and blue-grade tint to the slera caused by thinned scleral tissue. The blue tint of the slera is secondary to defective type 1 collagen, which shows visualization of underlying choroidal veins. Elastin is a connective tissue protein composed of elastin and glycoprotein-microphibles that are found primarily in the lungs, arterial walls, and elastic ligaments. Elastin is synthesized from troppoelastin, a precursor protein. After secretion from the cell, troppoelastin deposits onto fibrillin. It is in fibrillin caused marfan syndrome. Marfan syndrome is noted by increased height, joint laxity, ectopia lentus, or lens displacement, cardiac abnormalities, including including aortic dilation and mitral valve prolapse. In the albioli, elastin is broken down by elastase from activated neutrophils. Alpha1 antitripsin and enzyme produced in the liver usually blocks elastase and protects the lungs. However, genetic defects in alpha1 antitripsin can lead to pulmonary amthazema at a young age because of increased breakdown of lung-connected tissue. Enzymes are protein catalysts. They have active sites which permit substrate binding. Stabilization of the transition state leads to decreased activation energy, leading to increased rates of substrate to product or reactionary, but no change in reaction equilibrium. Enzymes are described mathematically using the mechalus mentin kinetics. Be sure to check out figure 2.7 on page 22, which shows the mechalus mentin enzyme kinetics. Km is the substrate concentration at which the reaction is 1/2 Vmax. V is the velocity of the reaction and S is the substrate concentration. A higher Km means a lower affinity of the substrate for the enzyme. When S is much greater than Km, the rate of the reaction is independent of S. This is known as zero-order kinetics. When S equals Km, the initial velocity V equals Vmax over 2. When S is less than Km, the reaction rate is proportional to S. This is first-order kinetics. Vmax is the maximal reaction velocity. This occurs when the enzyme is saturated with substrate. A line-weaver birth plot is a double reciprocal plot of 1/V versus 1/S. This produces a straight line. The Y intercept is 1/Vmax and the X intercept is -1/Km. M kinetics are affected by inhibitors, which may be classified in several ways. Competitive inhibitors, Km is increased, Vmax is unchanged. There is always competition between two lines, so they always cross on the graph. Solute concentrations change, but velocity remains the same. Vmax intersects on the vertical axis, so Vmax is the same. Competitive inhibitors include methanol and ethylene glycol, which compete with ethanol or binding to alcoholadyhydrogenase. Giving a patient ethanol reduces methanol toxicity by competing for the enzyme active site, thereby slowing the build-up of toxic metabolites. For competitive inhibitors, high substrate concentration can reverse competitive inhibition because the enzyme is saturated with substrate. Non-competitive inhibitors, Km is unchanged, Vmax is decreased. Plots intersect on the horizontal axis, so Km is the same. Non-competitive inhibitors bind at a site distant from the active site and form unreactive complexes with the enzyme. Increased substrate amount does not change the level of inhibition. Vysosigmin, a colonestereous inhibitor, is a non-competitive inhibitor. A third kind of enzyme inhibitor is an irreversible inhibitor, which permanently inactivates enzymes. Examples include heavy metals, aspirin, and irreversible inhibitor of cycloxygenase, fluoroyersil, and organophosphates. The effect of irreversible inhibitors is only overcome by synthesis of new enzymes. Make sure to check out table 2.1 on page 23. It shows serum enzyme markers used for diagnosis. Hydrogen metabolism, disposal of amino acid nitrogen, free amino acids are produced by degradation of dietary protein, synthesis of non-essential amino acids, and degradation of body protein. Nitrogen is removed from amino acids because amino acids cannot directly take part in energy metabolism. Alfakito groups are removed from amino acids by two sequential reactions. Transaminases, such as alanine amino transferase, or ALT, and aspartate, amino transferase, or ASD, transfer amino groups to alfakito gluturate, producing an alfakito acid and glutamate. The alfakito acid can enter the citric acid cycle. No transferases require pyrodoxyl phosphate for function, a derivative of vitamin B6. Transaminases are intracellular enzymes found primarily in hepatic tissue. Thus, elevated serum levels of transaminases can be diagnostic for liver damage. Next, glutamate dehydrogenase oxidatively deaminates glutamate to alfakito gluturate and free ammonia. For NH3, the NH3 can be stored and transported to the liver as glutamine, or as alanine, as part of the glucose alanine cycle. Aspartate an ammonia, then enter the urea cycle. The broughty's primary method for disposing of amino groups from amino acids. The nitrogen of aspartate, CO2, and NH3 are incorporated into urea. The urea cycle is a 5-step metabolic pathway that takes place within the liver. It removes nitrogen waste from the amino groups of amino acids that occurs during protein turnover. The rate limiting step for the urea cycle is carbomorol phosphate synthetase 1, which is activated by anacetyl glutamate, which is synthesized from acetyl coenzyme A. Two molecules of NH3 and one of CO2 are converted into urea. Urea is then transported in the blood to the kidneys for excretion in the urine. Make sure to check out figure 2.9. It depicts an illustration of the urea cycle. Urea levels in patients with kidney failure are elevated. Urea is produced by bacteria and the gut creates a significant amount of ammonia, which can lead to hyperamonemia. New mice and refaxamin, orally administered, can reduce the number of urease-producing bacteria and are used in the treatment of hepatic encephalopathy. Hyperamonemia occurs when there are genetic defects of the urea cycle or liver disease. Ammonia has a toxic effect on the central nervous system, or CNS, causing tremors, cerebral dima, and blurring a vision. Urea cycle disorders are rare, and with the exception of exhaling-ornathine trans-carbamolase deficiency, which is the most common hereditary hyperamonemia, are inherited as autosomal recessive traits. Deficiencies of enzymes in the urea cycle cause intolerance to protein from the accumulation of ammonia in the body. These increased ammonia levels are toxic to the CNS and can lead to coma and death. These hereditary hyperamonemia disorders include those listed in table 2.2 on page 25. In each of these disorders, urea is unable to be synthesized, which leads to hyperamonemia during the first weeks after birth. Mental retardation is common. Treatment of these disorders includes protein limitation in the diet and administration of compounds that bind covalently to amino acids so that they can be excreted in the urine. For example, phenyl butyrate, a pro drug that is metabolized to phenyl acetate, combines with glutamine to form phenyl acetyl glutamine, which can be excreted in the urine. This assists in clearance of nitrogen from the blood. Ammonia acid synthesis and degradation, although essential amino acids must be obtained for the diet. Non-essential amino acids can be synthesized by several different pathways. Aspartate, alanine, and glutamate are synthesized from transamination of alpha-keto acids. Aspartate is derived from oxaloacetate, glutamate from alpha-ketogluerate, and alanine from pyruvate. Glutamine and asparagine are synthesized by amidation. Glutamine synthetase forms glutamine from glutamate. reaction also. helps to reduce ammonia levels. Asparegine synthetase forms asparegine from aspartate. Serine is synthesized from the glycolysis intermediate three phosphoglycerate. Blycine in turn can be synthesized from serine. Proline is synthesized from glutamate. Argenine is synthesized from citralline, an intermediate of the ureocycle. Two amino acids can be synthesized from essential amino acids. Hystine is synthesized from homocysteine and serine. Homocysteine is derived from methionine. Tyrazine is synthesized by phenylalanine hydroxylase. This reaction requires tetrahydrobiobterine or BH4. Because tyrazine and cystine are formed from essential amino acids, tyrazine and cystine are only essential amino acids in the presence of adequate dietary intake of methionine and phenylalanine. While amino acids are catabolized, the alpha amino group is removed and enters the ureocycle for excretion, while the carbon skeleton is metabolized. Amino acids are classified as glucogenic, ketogenic or both based on which intermediates are produced during catabolism. Glucogenic amino acids yield pyruvate or one of the intermediates of the tri-carboxylic acid or TCA cycle. Oxaloacetate, alpha-queue gluturate, succinyl-coa, or fumerate, when they are catabolized. This yields lipids and energy in addition to glucose. Most amino acids are exclusively glucogenic. Cutogenic amino acids yield acetoacetate or one of its precursors such as aceto-coa or aceto-aceto-aceto-coa, providing lipids and energy. Lucene and lysine, the two exclusively ketogenic amino acids, cannot therefore produce glucose or glycogen in the liver or glycogen in muscle. Four amino acids are both glucogenic and ketogenic. These include isolucine, phenylalanine, triptophane, and tyrosine. Here 210 on page 26 depicts the location at which each amino acid is integrated into the TCA cycle. Several important disorders arise in patients with deficiencies in the enzymes of amino acid synthesis and degradation pathways, including maple syrup urine disease, albinism, and PKU. Be sure to check out Figure 211 on page 27. It depicts an illustration and pathway representing the disorders of amino acid metabolism. PKU is a common disease of amino acid metabolism that can be effectively treated through changes and diet. PKU is caused by a deficiency of phenylalanine hydroxylase. Patients are characterized by a deficiency of tyrosine and elevated phenylalanine. High levels of phenylalanine lead to elevated levels of phenylalanine metabolites, such as phenylactate, phenylacetate, and phenyl pyruvate, which give the body and urine a characteristic musty or mousy odor. Clinically patients with PKU have mental retardation, seizures, tremor, microcephaly, and failure to thrive. Pocuses of mental retardation start by age 1. The first step in the pigment melanin formation is hydroxylation of tyrosine by tyrosinase, which is competitively inhibited by high levels of phenylalanine and PKU. Because of this, patients with PKU often have hypopigmentation, or fair hair, blue eyes, and light colored skin. Polys� screening and diagnosis are critical because PKU can be treated by diet. However, newborns with PKU may have normal phenylalanine levels at birth, owing to maternal transfer. Therefore, screening tests are typically done at least one to two days after birth. Albinism is a group of conditions in which there is a deficiency in melanin production caused by a defect in tyrosine metabolism. Helping decrease pigmentation of the eyes, hair, and skin. The most severe kind of albinism is called complete albinism and is caused by a complete lack of tyrosinase activity. Ocaptoneuria is a disorder caused by the deficiency of homogenitistic acid oxidase, an enzyme in the pathway that degrades tyrosine. This leads to the accumulation of homogenitistic acid, causing homogenitistic acid urea, in which the patient's urine has an elevated level of homogenitistic acid. When allowed to stand, the homogenitistic acid in the urine is oxidized to a dark pigment. Patients with alcaptoneuria also exhibit arthritis of large joints and black pigmentation of cartilage and collagen. Albin includes diets low in phenylalanine and tyrosine, although this is not a life threatening disorder, arthritis may be severe. Maple syrup urine disease is an autosomal recessive disorder in which there is a deficiency, branch, chain, alfakido acid dehydrogenase. The inability to oxidatively decarboxylate the branch chain amino acids, lucine, valine, isolucine, leads to a buildup of alfakido isocapyrac acid, alfakido isovaleric acid, and alfakido beta-methylvaleric acid respectively. This leads to a buildup of branch chain alfakido acids in the urine, causing a sweet odor. They also accumulate in the blood, leading to toxic effects on the brain. Typically, symptoms present within a few days of birth and include vomiting, severe metabolic acidosis, and a maple syrup odor to the urine. Treatment is with formula with reduced levels of lucine, valine, and isolucine. However, branch chain amino acids are important in growth, so low levels are present in the formula. Homocystinuria is a group of autosomal recessive disorders caused by abnormal homocystine metabolism. Patients have high levels of homocystine and methyenine in the urine, but a low level of cysteine. One important enzyme involved in homocystine metabolism, cystothyanine beta-synthase, is mutated in a common form of homocystinuria. Without cystothyanine beta-synthase, to convert homocystine to cystothyanine, patients have etypia-lensis, osteoporosis, and mental retardation. In addition to early vascular disease, some patients can improve with treatment with pyrodoxine or vitamin B6, a coenzyme of cystothyanine beta-synthase. Intimid of homocystinuria also includes reduced intake of methyenine and administration of vitamin supplements. Other disorders can also arise from genetic mutations in enzymes important in the amino acid metabolism pathways. These include tyrosinemia type 1, methamelonic co-ay mutate stificiency, histidemia, and cystothyanuria, a summary of several important hereditary disorders is included in table 2.3 on page 28. Be sure to check out figure 2.11. It depicts an illustration of the pathways of disorders of amino acid metabolism. Amino acid derivatives. In addition to their role in proteins, amino acids are the precursors of many nitrogen-containing molecules, such as pyrimidines, purines, chem, neurotransmitters, and other small molecules. Figure 2.12 depicts the synthetic pathway of the catacolamines dopamine, norpinephrine, in epinephrine, from tyrosine. The synthetic pathway occurs primarily in the CNS, peripheral ganglia, and the adrenal medulla. First, tyrosine is hydroxylated by tyrosine hydroxylase into dopamine, a reaction that requires tetrahydrobiopterin or BH4. Second, dopamine is decarboxylated, forming dopamine. Dopamine levels are reduced in Parkinson's disease. One treatment for Parkinson's disease is LDopa, the precursor to dopamine. The chloropinephrin is formed by hydroxylation of dopamine, and epinephrine is then formed by methylation. The degradation of catacolamines is shown in figure 2.13. Two enzymes are critical in catacolamine degradation, monomine oxidase, or MAO, and catacol O-methodranspiration, or COM2. of vanilla acid. and Vanille Mandelic acid are excreted in the urine. The cataclycloum in breakdown pathway is important in two different clinical scenarios. M.A.O. inhibitors, or M.A.O.I.s, are a class of medication used to treat depression. M.A.O.I.s can inhibit the breakdown of amines and the diet, which can cause hypertensive crisis if an individual taking an M.A.O.I also consumes foods containing the sympathomimatic tyramine, such as cheese. Neroendocrine tumors of the adrenal medulla are known as fiochromocytomas. The tumorous chromofin cells secrete large amounts of catacolomines, leading to elevated heart rate, elevated blood pressure, and sweating. Diagnosis of fiochromocytoma includes measuring plasma for catacolomines and metanephrens, or urine, for Vanille Mandelic acid, or V.M.A. Neroblastoma also produce elevated levels of catacolomines and are tested for in a similar manner. The synthesis and breakdown of serotonin, also called 5 hydroxy-tryptamine, or 5HT, is important in the balance of serotonin in the body. Triptophane is hydroxylated to form 5HTP, which is then decarboxylated to form serotonin. Serotonin is degraded by M.A.O. to 5 hydroxy-indole acetic acid, or 5HIA. The presence of high levels of 5HIA in the urine is diagnostic of cancers that produce large amounts of serotonin. For example, carcinoid tumors. Several other important nitrogen-containing molecules are synthesized from amino acids. Melonin, the pigment, is synthesized from tyrazine in melanocytes. Nitrogen oxide, or NO, and neurotransmitter, plays a role in macrophage function and relaxes vascular spude muscle, causing vasodilation. NO is synthesized from arginine by NO synthase. Be sure to check out Figure 2.13. It depicts the degradation of catacolamines with major degradation products. Also be sure to check out Figure 2.14. It depicts seroton synthesis and degradation. 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.