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Plasma proteins


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Plasma proteins- Chemistry, functions and clinical significance

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Plasma proteins

  1. 1. Biochemistry For Biochemistry For Medics 7/11/2012 1
  2. 2. Plasma consists of water, electrolytes,metabolites, nutrients, proteins, and hormones.The concentration of total protein in humanplasma is approximately 6.0–8.0 g/dL andcomprises the major part of the solids of theplasma.The proteins of the plasma are a complexmixture that includes not only simple proteinsbut also conjugated proteins such asglycoproteins and various types of lipoproteins. Biochemistry For Medics 7/11/2012 2
  3. 3. Biochemistry For Medics 7/11/2012 3
  4. 4. Salting-out methods-three major groups—fibrinogen, albumin, and globulins—by theuse of varying concentrations of sodium orammonium sulfate.Electrophoresis- five major fractionsAlbuminα1 and α2 globulinsβ globulins γ globulins Biochemistry For Medics 7/11/2012 4
  5. 5. Biochemistry For Medics 7/11/2012 5
  6. 6. Albumin (69 kDa) is the major protein ofhuman plasma (3.4–4.7 g/dL)Makes up approximately 60% of the totalplasma protein.About 40% of albumin is present in theplasma, and the other 60% is present in theextracellular space.Half life of albumin is about 20 days.Migrates fastest in electrophoresis atalkaline pH and precipitates last in saltingout methods Biochemistry For Medics 7/11/2012 6
  7. 7. The liver produces about 12 g of albuminper day, representing about 25% of totalhepatic protein synthesis and half itssecreted protein.Albumin is initially synthesized as apreproproteinIts signal peptide is removed as it passesinto the cisternae of the rough endoplasmicreticulum, and a hexapeptide at the resultingamino terminal is subsequently cleaved offfarther along the secretory pathway. Biochemistry For Medics 7/11/2012 7
  8. 8. Mature human albumin consists of onepolypeptide chain of 585 amino acids andcontains 17 disulfide bondsIt has an ellipsoidal shape, which meansthat it does not increase the viscosity of theplasma as much as an elongated moleculesuch as fibrinogen does.Has a relatively low molecular mass about69 kDaHas an iso-electric pH of 4.7 Biochemistry For Medics 7/11/2012 8
  9. 9.  Colloidal osmotic Pressure-albumin isresponsible for 75–80% of the osmoticpressure of human plasma due to its lowmolecular weight and large concentrationIt plays a predominant role in maintainingblood volume and body fluid distribution.Hypoalbuminemia leads to retention of fluidin the tissue spaces(Edema) Biochemistry For Medics 7/11/2012 9
  10. 10. Transport function-albumin has an ability tobind various ligands, thus acts as atransporter for various molecules. Theseinclude- free fatty acids (FFA),calcium,certain steroid hormones,bilirubin,copperA variety of drugs, including sulfonamides,penicillin G, dicoumarol, phenytoin andaspirin, are also bound to albumin Biochemistry For Medics 7/11/2012 10
  11. 11. Nutritive FunctionAlbumin serves as a source of amino acids fortissue protein synthesis to a limited extent,particularly in nutritional deprivation of aminoacids. Buffering Function-Among the plasmaproteins, albumin has the maximum bufferingcapacity due to its high concentration and thepresence of large number of histidine residues,which contribute maximally towardsmaintenance of acid base balance.Viscosity- Exerts low viscosity Biochemistry For Medics 7/11/2012 11
  12. 12. Blood brain barrier- Albumin- free fattyacid complex can not cross the blood brainbarrier, hence fatty acids can not be utilizedby the brain.Loosely bound bilirubin to albumin can beeasily replaced by drugs like aspirinIn new born if such drugs are given, thereleased bilirubin gets deposited in braincausing Kernicterus. Biochemistry For Medics 7/11/2012 12
  13. 13. Protein bound calcium Calcium level is lowered in conditions ofHypo- Albuminemia Serum total calcium may be decreased Ionic calcium remains sameTetany does not occurCalcium is lowered by 0.8 mg/dl for a fall of1g/dl of albumin Biochemistry For Medics 7/11/2012 13
  14. 14. Drug interactions—Two drugs having same affinity for albuminwhen administered together, can compete foravailable binding sites with consequentdisplacement of other drug, resulting inclinically significant drug interactions.Example-Phenytoin, dicoumarol interactions Biochemistry For Medics 7/11/2012 14
  15. 15. Edema- Hypoalbuminemia results in fluidretention in the tissue spacesNormal level- 3.5-5 G/dlHypoalbuminemia- lowered level is seen in thefollowing conditions-Cirrhosis of liverMalnutritionNephrotic syndromeBurnsMalabsorptionAnalbuminemia- congenital disorderHyperalbuminemia- In conditions of fluiddepletion(Haemoconcentration) Biochemistry For Medics 7/11/2012 15
  16. 16. Globulins are separated by half saturationwith ammonium sulphateMolecular weight ranges from 90,000 to13,00,000By electrophoresis globulins can beseparated in to –α1-globulinsα2-globulinsβ-globulins Y-globulins Biochemistry For Medics 7/11/2012 16
  17. 17. α and β globulins are synthesized in theliver.Y globulins are synthesized in plasma cellsand B-cells of lymphoid tissues (Reticulo-endothelial system)Synthesis of Y globulins is increased inchronic infections, chronic liver diseases,auto immune diseases, leukemias,lymphomas and various other malignancies. Biochemistry For Medics 7/11/2012 17
  18. 18.  They are glycoproteinsBased on electrophoretic mobility , they aresub classified in to α1 and α2 globulinsα1 globulinsExamples-α1antitrypsinOrosomucoid (α1 acid glycoprotein)α1-fetoprotein (AFP) Biochemistry For Medics 7/11/2012 18
  19. 19. α1-antitrypsinAlso called α1-antiproteaseIt is a single-chain protein of 394 amino acids,contains three oligosaccharide chains It is the major component (> 90%) of the α 1fraction of human plasma. It is synthesized by hepatocytes andmacrophages and is the principal serine proteaseinhibitor of human plasma. It inhibits trypsin, elastase, and certain otherproteases by forming complexes with them. Biochemistry For Medics 7/11/2012 19
  20. 20. At least 75 polymorphic forms occur, manyof which can be separated by electrophoresisThe major genotype is MM, and itsphenotypic product is PiMA deficiency of this protein has a role incertain cases (approximately 5%) ofemphysema.This occurs mainly in subjects with the ZZgenotype, who synthesize PiZ, and also inPiSZ heterozygotes, both of whom secreteconsiderably less protein than PiMMindividuals. Biochemistry For Medics 7/11/2012 20
  21. 21. Emphysema-Normally antitrypsinprotects the lungtissue fromproteases(activeelastase) released frommacrophagesForms a complexwith protease andinactivates it.In its deficiency, theactive elastasedestroys the lungtissue by proteolysis. Biochemistry For Medics 7/11/2012 21
  22. 22. Smoking and Emphysema-A methionine(residue 358) of α1-antitrypsin is involved in itsbinding to proteases.Smoking oxidizes this methionine tomethionine sulfoxide and thus inactivates it.Affected molecules of α1-antitrypsin no longerneutralize proteases.This is particularly devastating in patients (eg,PiZZ phenotype) who already have low levels ofα1-antitrypsin.The further diminution in α 1-antitrypsinbrought about by smoking results in increasedproteolytic destruction of lung tissue,accelerating the development of emphysema. Biochemistry For Medics 7/11/2012 22
  23. 23. Biochemistry For Medics 7/11/2012 23
  24. 24. Cirrhosis of Liver- In this condition, moleculesof the ZZ phenotype accumulate and aggregatein the cisternae of the endoplasmic reticulum ofhepatocytes.Aggregation is due to formation of polymers ofmutant α 1-antitrypsin, the polymers forming viaa strong interaction between a specific loop inone molecule and a prominent -pleated sheet inanother (loop-sheet polymerization). By mechanisms that are not understood,hepatitis results with consequent cirrhosis(accumulation of massive amounts of collagen,resulting in fibrosis). Biochemistry For Medics 7/11/2012 24
  25. 25. Biochemistry For Medics 7/11/2012 25
  26. 26.  Concentration in plasma- 0.6 to 1.4 G/dlCarbohydrate content 41%Marker of acute inflammationActs as a transporter of progesteroneTransports carbohydrates to the site oftissue injury Concentration increases in inflammatorydiseases, cirrhosis of liver and in malignantconditionsConcentration decreases in liver diseases,malnutrition and in nephrotic syndrome Biochemistry For Medics 7/11/2012 26
  27. 27. Present in high concentration in fetal bloodduring mid pregnancyNormal concentration in healthy adult-< 1µg/100mlLevel increases during pregnancyClinically considered a tumor marker for thediagnosis of hepatocellular carcinoma orteratoblastomas. Biochemistry For Medics 7/11/2012 27
  28. 28. important α2-globulins are- Clinically Haptoglobin Ceruloplasmin α2- macroglobulins Biochemistry For Medics 7/11/2012 28
  29. 29. Itis a plasma glycoprotein that bindsextracorpuscular hemoglobin (Hb) in a tightnoncovalent complex (Hb-Hp).The amount of Haptoglobin in humanplasma ranges from 40 mg to 180 mg ofhemoglobin-binding capacity per deciliter.The function of Hp is to prevent loss of freehemoglobin into the kidney. This conservesthe valuable iron present in hemoglobin,which would otherwise be lost to the body. Biochemistry For Medics 7/11/2012 29
  30. 30. The molecular mass of hemoglobin isapproximately 65 kDaHb-Hp complex has a molecular mass ofapproximately 155 kDa. Free hemoglobin passes through theglomerulus of the kidney, enters the tubules,and tends to precipitate therein (as can happenafter a massive incompatible blood transfusion,when the capacity of haptoglobin to bindhemoglobin is grossly exceeded).However, the Hb-Hp complex is too large topass through the glomerulus.Thus Hp helps to conserve iron. Biochemistry For Medics 7/11/2012 30
  31. 31. Concentration rises in inflammatory conditionsConcentration decreases hemolytic anemiasHalf-life of haptoglobin is approximately 5days, the half-life of the Hb-Hp complex isabout 90 minutes, the complex being rapidlyremoved from plasma by hepatocytes.Thus, when haptoglobin is bound tohemoglobin, it is cleared from the plasma about80 times faster than normally.The level of haptoglobin falls rapidly inhemolytic anemias.Free Hp level or Hp binding capacity depictsthe degree of intravascular hemolysis. Biochemistry For Medics 7/11/2012 31
  32. 32.  Copper containing α2-globulin Glycoprotein with enzyme activitiesIt has a blue color because of its highcopper contentCarries 90% of the copper present inplasma.Each molecule of ceruloplasmin binds sixatoms of copper very tightly, so that thecopper is not readily exchangeable. Biochemistry For Medics 7/11/2012 32
  33. 33. Normal plasma concentration approximately30mg/dL Enzyme activities are Ferroxidase, copperoxidase and Histaminase.Synthesized in liver in the form of apoceruloplasmin, when copper atoms get attached itbecomes Ceruloplasmin. Although carries 90% of the copper present inplasma. but it binds copper very tightly, so thatthe copper is not readily exchangeable.Albumin carries the other 10% of the plasmacopper but binds the metal less tightly than doesceruloplasmin.Albumin thus donates its copper to tissues morereadily than ceruloplasmin and appears to be moreimportant than ceruloplasmin in copper transportin the human body. Biochemistry For Medics 7/11/2012 33
  34. 34. Normal level- 25-50 mg/dlLow levels of ceruloplasmin are found inWilson disease (hepatolenticulardegeneration), a disease due to abnormalmetabolism of copper.The amount of ceruloplasmin in plasma isalso decreased in liver diseases, mal nutritionand nephrotic syndrome. Biochemistry For Medics 7/11/2012 34
  35. 35. Major component of α2 proteinsComprises 8–10% of the total plasma protein inhumans.Tetrameric protein with molecular weight of725,000.Synthesized by hepatocytes and macrophagesInactivates all the proteases and thus is animportant in vivo anticoagulant.Carrier of many growth factorsNormal serum level-130-300 mg/dlConcentration is markedly increased in nephroticsyndrome, since other proteins are lost throughurine in this condition. Biochemistry For Medics 7/11/2012 35
  36. 36. β Globulins of clinical importance are – Transferrin C-reactive proteinHaemopexinComplement C1qβ Lipoprotein(LDL) Biochemistry For Medics 7/11/2012 36
  37. 37. Transferrin (Tf) is a β 1-globulin with a molecularmass of approximately 76 kDa. It is a glycoprotein and is synthesized in theliver.About 20 polymorphic forms of transferrin havebeen found.It plays a central role in the bodys metabolism ofiron because it transports iron (2 mol of Fe3+ permole of Tf) in the circulation to sites where iron isrequired, eg, from the gut to the bone marrow andother organs.Approximately 200 billion red blood cells (about20 mL) are catabolized per day, releasing about 25mg of iron into the body—most of which istransported by transferrin. Biochemistry For Medics 7/11/2012 37
  38. 38. There are receptors (TfR1 and TfR2) on the surfacesof many cells for transferrin.It binds to these receptors and is internalized byreceptor-mediated endocytosis.The acid pH inside the lysosome causes the iron todissociate from the protein.The dissociated iron leaves the endosome via DMT1to enter the cytoplasm.ApoTf is not degraded within the lysosome.Instead, it remains associated with itsreceptor, returns to the plasmamembrane, dissociates from its receptor, reentersthe plasma, picks up more iron, and again deliversthe iron to needy cells.Normally, the iron bound to Tf turns over 10–20times a day. Biochemistry For Medics 7/11/2012 38
  39. 39. Biochemistry For Medics 7/11/2012 39
  40. 40. The concentration of transferrin in plasma isapproximately 300 mg/dL.This amount of transferrin can bind 300 g ofiron per deciliter, so that this represents thetotal iron-binding capacity of plasma.However, the protein is normally only one-thirdsaturated with iron.In iron deficiency anemia, the protein is evenless saturated with iron, whereas in conditions ofstorage of excess iron in the body(eg, hemochromatosis) the saturation with iron ismuch greater than one-third. Biochemistry For Medics 7/11/2012 40
  41. 41. Increased levels are seen in iron deficiencyanemia and in last months of pregnancy Decreased levels are seen in-Protein energy malnutritionCirrhosis of liverNephrotic syndrome TraumaAcute myocardial infarctionMalignanciesWasting diseases Biochemistry For Medics 7/11/2012 41
  42. 42. So named because it reacts with C-polysaccharide of capsule of pneumococciMolecular weight of 115-140 kDSynthesized in liverCan stimulate complement activity andmacrophagesAcute phase protein- Concentration rises ininflammatory conditionsClinically important marker to predict therisk of coronary heart disease Biochemistry For Medics 7/11/2012 42
  43. 43.  Molecular weight 57,000-80,000Normal level in adults-0.5 to 1.0 gm/LLow level at birth, reaches adult value withinfirst year of lifeSynthesized in liverFunction is to bind haem formed frombreakdown of Hb and other haemoproteinsLow level- found in hemolytic disorders, atbirth and drug inducedHigh level- pregnancy, diabetes mellitus,malignancies and Duchenne muscular dystrophy Biochemistry For Medics 7/11/2012 43
  44. 44. First complement factor to bind antibodyBinding takes place at the Fc region of IgG or IgMBinding triggers the classical complementpathwayThermo labile, destroyed by heatingNormal level – 0.15 gm/LMolecular weight-400,000Can bind heparin and bivalent ionsDecreased level is used as an indicator ofcirculating Ag –Ab complex. High levels are found in chronic infections Biochemistry For Medics 7/11/2012 44
  45. 45.  They are immunoglobulins with antibodyactivityThey occupy the gamma region onelectrophoresisImmunoglobulins play a key role in thedefense mechanisms of the bodyThere are five types of immunoglobulinsIgG, IgA, IgM, IgD, and IgE. Biochemistry For Medics 7/11/2012 45
  46. 46. Biochemistry For Medics 7/11/2012 46
  47. 47. Immunoglobulin Major FunctionsIgG Main antibody in the secondary response. Opsonizes bacteria, Fixes complement, neutralizes bacterial toxins and viruses and crosses the placenta. Secretory IgA prevents attachment ofIgA bacteria and viruses to mucous membranes. Does not fix complement. Produced in the primary response to an antigen. Fixes complement. DoesIgM not cross the placenta. Antigen receptor on the surface of B cells.IgD Uncertain. Found on the surface of many B cells as well as in serum.IgE Mediates immediate hypersensitivity Defends against worm infections. Does Biochemistry For Medics 7/11/2012 47
  48. 48. Also called clotting factor1Constitutes 4-6% of total proteinPrecipitated with 1/5 th saturation with ammoniumsulphateLarge asymmetric moleculeHighly elongated with axial ratio of 20:1Imparts maximum viscosity to bloodSynthesized in liverMade up of 6 polypeptide chainsChains are linked together by S-S linkagesAmino terminal end is highly negative due to thepresence of glutamic acidNegative charge contributes to its solubility inplasma and prevents aggregation due to electrostaticrepulsions between the fibrinogen molecules. Biochemistry For Medics 7/11/2012 48
  49. 49. Name Compounds transportedAlbumin Fatty acids, bilirubin, hormones, calcium, heavy metals, drugs etc.Prealbumin-(Transthyretin) Steroid hormones thyroxin, RetinolRetinol binding protein Retinol (Vitamin A)Thyroxin binding protein(TBG) ThyroxinTranscortin(Cortisol binding protein) Cortisol and corticosteroidsHaptoglobin HemoglobinHemopexin Free haemTransferrin IronHDL(High density lipoprotein) Cholesterol (Tissues to liver)LDL(Low density lipoprotein) Cholesterol(Liver to tissues) Biochemistry For Medics 7/11/2012 49
  50. 50. The levels of certain proteins may increase inblood in response inflammatory andneoplastic conditions, these are called Acutephase proteins. Examples-C- reactive proteinsCeruloplasminAlpha -1 antitrypsinAlpha 2 macroglobulinsAlpha-1 acid glycoprotein Biochemistry For Medics 7/11/2012 50
  51. 51. The levels of certain proteins are decreasedin blood in response to certain inflammatoryprocesses.Examples-AlbuminTransthyretinRetinol binding proteinTransferrin Biochemistry For Medics 7/11/2012 51
  52. 52. 1) Bence – Jone’s proteinsAbnormal proteins- monoclonal light chainsPresent in the urine of a patient suffering from multiplemyeloma (50% of patients)Molecular weight 45,000Identified by heat coagulation testBest detected by zone electrophoresis andimmunoelectrophoresis2)CryoglobulinsThese proteins coagulate when serum is cooled to verylow temperatureCommonly monoclonal IgG or IgM or bothIncreased in rheumatoid arthritis, multiple myeloma,lymphocytic leukemia, lymphosarcoma and systemic lupuserythematosus Biochemistry For Medics 7/11/2012 52
  53. 53. NutritiveFluidexchangeBufferingBinding and transportEnzymesHormonesBlood coagulationViscosityDefenseReserve proteinsTumor markersAntiproteases Biochemistry For Medics 7/11/2012 53
  54. 54. Hyperproteinemia- Levels higher than 8.0gm/dl Causes- Hemoconcentration- due to dehydration,albumin and globulin both are increasedAlbumin to Globulin ratio remains same.Causes- Excessive vomitingDiarrheaDiabetes InsipidusPyloric stenosis or obstructionDiuresisIntestinal obstruction Biochemistry For Medics 7/11/2012 54
  55. 55. 1)Polyclonal- Chronic infections Chronic liver diseases Sarcoidosis Auto immune diseases2) Monoclonal Multiple myeloma Macroglobulinaemia Lymphosarcoma Leukemia Hodgkin’s disease Biochemistry For Medics 7/11/2012 55
  56. 56. Decease in total protein concentrationHemodilution- Both Albumin and globulins aredecreased, A:G ratio remains same, as in waterintoxication Hypoalbuminemia- low level of Albumin inplasmaCauses-Nephrotic syndromeProtein losing enteropathySevere liver diseasesMal nutrition or malabsorptionExtensive skin burnsPregnancy Malignancy Biochemistry For Medics 7/11/2012 56
  57. 57. Losses from body- same as albumin- throughurine, GIT or skinDecreased synthesisTransient neonatal Primary genetic deficiencySecondary – drug induced (Corticosteroidtherapy), uremia, hematological disordersAIDS(Acquired Immuno deficiency syndrome) Biochemistry For Medics 7/11/2012 57