Biochemistry Sheet 26 PDF

26 Nahla Ayad Layan Alnaimat Nafez Abutarboush 1  Plasma proteins Synthesis of plasma proteins Most of plasma proteins (albumin and globulins) are synthesized in the liver, the only exception is gamma globulins which are immunoglobulins which are a pr...

26 Nahla Ayad Layan Alnaimat Nafez Abutarboush 1  Plasma proteins Synthesis of plasma proteins Most of plasma proteins (albumin and globulins) are synthesized in the liver, the only exception is gamma globulins which are immunoglobulins which are a product of plasma cells that are mature B lymphocytes that are synthesized in the bone marrow, spleen and lymph nodes. *Plasma proteins are synthesized as preproproteins (immature cells) Why? This provides protection for the tissues synthesizing the proteins (which may be enzymes) by keeping them in an inactive form, ready for activation when needed. If they were always active, it could be harmful to the cell, as they are synthesized in tissues different from their site of action. Preproproteins are immature proteins that need 2 signaling processes to be matured, while the protein that needs 1 signaling process is called proprotein. These proteins undergo many posttranslational modifications, time from the start of synthesis till evacuation into the plasma membrane varies depending on the type of protein)30 min to several hours), they are mostly glycoproteins (N- or O-linked) except for albumin due to viscosity of the blood. Polymorphism and Half lives Plasma proteins exhibit polymorphism and have varying half-lives. The half-life of each plasma protein depends on its type and function and can change upon binding to other molecules. 2  These half-lives are determined through isotope labeling studies (e.g., using I131). Albumin has a half-life of 20 days Haptoglobin has a half-life of 5 days In diseases, the half-life of plasma proteins can be affected. In conditions such as protein-losing gastroenteropathy—diseases affecting the gastrointestinal (GI) tract—proteins may be lost when plasma proteins exit the vascular system and enter the GI tract. This occurs as endothelial cells lining the GI tract become more separated, allowing proteins to escape. For instance, in Crohn’s disease, the half-life of albumin may be reduced by one day. ‫نصف عمر‬protein -losing gastroenteropathy)، ( ‫ مثل أمراض فقدان البروتين من الجهاز الهضمي‬،‫في بعض األمراض‬ ‫بروتينات البالزما بتأثر والسبب هو أنه البروتينات ب تخرج من األوعية الدموية إلى الجهاز الهضمي نتيجة تباعد الخاليا المبطنة للجهاز‬. ‫ فبيسمح بتسرب البروتينات‬،‫الهضمي‬.‫ نصف عمر األلبومين ينخفض بمقدار يوم واحد بسبب فقدانه السريع‬،) Crohn’s disease( ‫ في مرض كرون‬:‫مثال‬ When a protein experiences a mutation that changes its gene sequence slightly, the protein can still perform its function. However, the mutation may have different effects: it could improve the protein’s performance, reduce its efficiency, or have no impact at all. If this mutation is passed down to offspring and continues to spread through generations, it can become more common. When the mutation is found in more than 1% of the population, it is called polymorphism. perform it ❖ Most of plasma proteins are affected by polymorphisms in multiple forms like the Alpa 1-antitrypsin, haptoglobin, transferrin, ceruplasmin and immunoglobulins. ❖ ABO blood grouping is a form of polymorphism(the best known). ❖ Polymorphism does not necessarily cause a disease. ❖ A mendelian or monogenic trait ❖ Exists in population in at least two phenotypes,neither is rare ❖ Electrophoresis or isoelectric focusing‫تقنيات بتساعد في دراسه البروتينات‬ 3 General and specific functions of plasma proteins: Every plasma protein has a specific function however they all share general functions which are: 1. Nutritive Role: broken down for energy 2. Maintenance of blood pH: helping the blood buffering capacity,as each protein has a free amide and carboxyl group that aid in buffering. (Amphoteric property) 3. Contributes to blood viscosity: all proteins increase viscosity of the blood, even albumin although it is not glycoprotein. 4. Maintenance of blood osmotic pressure: the force exerted from proteins on water to keep water around. Specific function: 1. Enzymes: rennin, coagulation factors, lipases 2. Humoral immunity: immunoglobulins 3. Blood coagulation factors 4. Hormonal: erythropoietin 5. Transport proteins: transferrin, thyroxin binding globulin, apolopoprotein. Starling Forces Proteins are typically confined to the vascular system and are not allowed to exit. Blood pressure is the force exerted by blood on the walls of blood vessels, and this force works to push water out of the vessels. In contrast, proteins exert an opposing force, helping to retain water within the vessels because proteins are soluble in the blood, thus preventing excessive water loss.‫ حيث يساعد‬،‫البروتينات تبقى داخل األوعية الدموية‬.‫ضغط الدم على دفع الماء خارج األوعية بينما البروتينات تسحب الماء للحفاظ عليه داخل األوعية‬ 4 -When Starling forces are exerted, blood pressure works to push water out of the vessels, creating a difference in blood pressure from when it leaves the heart until it reaches the capillaries. - At the arterial end of the capillaries, the hydrostatic pressure ( ‫(بطلع‬ ‫المي لبرا‬is 40 mmHg, while the oncotic pressure (the pressure that tries to keep water around proteins) is 25 mmHg. The net result is a 15 mmHg pressure outside the vessels at the arterial end. -At the venous end, the oncotic pressure remains the same at 25 mmHg (since no proteins are lost), while the hydrostatic pressure decreases due to the loss of fluid, dropping to 10 mmHg. The net result here is a 15 mmHg pressure inside the vessels. Therefore, the fluid and waste that left are returned with minimal change. -If the difference between what left and what returned is 1-2 mmHg, there is no problem. However, if more fluid leaves than returns, it can lead to excess fluid accumulation in tissues, causing edema _________________________________________________________________ Acute-phase proteins Proteins which increase in their magnitude and concentration in a dramatic way in cases of chronic and acute inflammation, tissue damage and cancer, levels increase from 0.5-1000 folds. When cytokines like interleukin-1 (IL-1) bind to their receptors and activate Nuclear Factor kappa-B (NF-kB), which is an expression factor in the cytosol and inactive, it becomes activated. Once 5 activated, NF-kB translocates to the nucleus and binds to the genes of certain plasma proteins, leading to increased messenger RNA production and, consequently, higher protein levels. Examples of these proteins include: C-reactive protein (CRP) Alpha 1-antitrypsin Haptoglobin Fibrinogen These proteins are called positive acute-phase proteins, as their concentrations increase in response to acute and chronic inflammation, tissue damage, and cancer. On the other hand, negative acute-phase proteins do not increase in concentration or may relatively decrease during acute and chronic inflammation, tissue damage, and cancer. Examples include: Pre-albumin Albumin Transferrin The reason these are called negative is that, with the increase in positive acute-phase proteins, the body reduces the concentration of negative proteins to maintain the overall function of plasma proteins. _____________________________________________________ Albumin Albumin is the major protein in human plasma, with a size of 69 kDa and a half-life of 20 days. It is synthesized as a preproprotein in an inactive 6 form, requiring two signaling processes to become active. After the signal peptide is removed, it is called proalbumin, and once a hexapeptide is cleaved, it becomes the active form, albumin. Albumin undergoes post-translational modifications, where proteases divide it into three different domains: 1A & 1B 2A & 2B 3A & 3B However, it does not form three separate polypeptide chains. It is synthesized as a single chain and is a monomeric protein composed of 585 amino acids. To maintain its final structure, albumin has 17 disulfide bonds. Albumin is highly negatively charged, with about 20 negative charges, which helps it maintain an ellipsoidal (oval) shape. This shape increases its surface area, exposing more amino acids on the surface, which is important for its function. At pH 7.4, albumin is anionic. Albumin is the primary contributor to osmotic pressure, making up 75-80% of the osmotic pressure in the blood. The liver synthesizes about 12g of albumin per day, which accounts for 25% of total protein synthesis. Albumin levels are used in liver function tests, where the production and breakdown of albumin are measured to assess liver function. However, the long half-life of albumin (20 days) limits its accuracy for assessing short-term liver function changes. 7 Albumin binding capacity Albumin is the major transporter of many molecules in the body, binding to various ligands such as: Free fatty acids (FFA) Certain steroid hormones Bilirubin (a yellow pigment produced when heme is broken down, which causes jaundice) Plasma tryptophan Metals like calcium, copper, and heavy metals Drugs like sulfonamides, penicillin G, dicumarol, and aspirin (leading to potential drug-drug interactions). This means that two drugs might bind to the same site on albumin, leading to drug-drug interactions. Since albumin is the primary transporter for many drugs, drugs exist in two forms: Free form: This form can leave the plasma and move into tissues. Bound form: This form remains bound to albumin in the plasma. If two drugs bind to the same site on albumin, it could displace one another, potentially altering their effectiveness or causing adverse effects _____________________________________________________ Analbuminemia Problems that occur where albumin is not present so the band for albumin in gel electrophoresis is not shown. It is a rare genetic disease that is autosomal recessive 8 inheritance, that is not fatal because the specific functions of albumin is lost but the general function of all plasma proteins is maintained but compromised by increasing the other plasma proteins. Patients have moderate edema due to increase in oncotic pressure as other proteins compensate the loss of albumin. Other clinical disorders 1. Hypoalbiminemia: is the decrease in the concentration of albumin, when the level in blood is less than 2 g/dl. This could be caused by a problem in the liver so the edema will be in the abdomin but if the problem is general the edema is general, Cirrhosis causing ascites (fluid in the abdominal cavity), in starvation and malnutrition the edema is generalized, nephrotic syndrome: affects the kidneys and patients that have renal failure, gastrointestinal loss of proteins. 2. Hyperalbuminemia: increase in albumin and occurs when dehydration is caused so water is decreased and proteins increase and compensated by hydration and when a patient has cancer where cells increase so more proteins will be produced. 3. Drug-drug interactions 4. Bilirubin toxicity: Aspirin should not be given to newborns because both bilirubin and aspirin compete for the same binding site on albumin. In newborns, bilirubin levels can be elevated, causing jaundice. When aspirin is given, it competes with bilirubin for albumin binding, leading to an increase in bilirubin concentration in the blood and its release from the vascular system. Since the blood-brain 9  barrier is not fully developed in newborns, bilirubin can enter the brain, where it accumulates in brain cells, causing kernicterus (bilirubin buildup in the brain). The brain cells cannot remove the bilirubin, which results in mental retardation, a condition known as Reye’s syndrome. ‫ال يجب إعطاء األسبرين للرضع ألن البيليروبين يتنافس مع األسبرين على االرتباط‬ ‫ مما يسبب تراكم البيليروبين في الدماغ‬،‫باأللبومين‬.‫ويؤدي إلى كِيرنيكتيروس و متالزمة راي‬ 5. Phenytoin-dicoumarol interaction: dicoumarol is an anticoagulant, while warfarin and phenytoin are anti convulsion drug and since they bind on the same place this may cause an interaction so they should not be given together. ‫معلش ياخوان الشيت طويل وفيه حكي كثير بس‬ ‫كله حكي الدكتور وشرحه بالمحاضره هللا يقوينا‬ 🦷❤️ ‫ويعيينا هالمواد وموفقين يارب‬ 🙏🏻🙏🏻 ‫ادعولنا‬ ‫تمت كتابة هذا الشيت عن روح والدة زميلنا عمرو رائد من دفعة تيجان‬ ‫دعواتكم لها بالرحمة والمغفرة‬ 10