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LECTURER ALEXANDER KOVAL, PHDGENERAL, BIOORGANIC CHEMISTRY ANDBIOCHEMISTRY DEPT.

CONTENTS SUBJECT AND TASKS OF MEDICAL BIOCHEMISTRY. GENERAL CHARACTERISTICS OF THE PROTEIN BIOSYNTHESIS, PROCESSING, AND PROTEINFOLDING. REPORT SPATIAL PROTEIN STRUCTURE AS A BASIS OF CONFORMATIONAL DISEASES. REPLACEMENT OF INDIVIDUAL AMINO ACIDS, AS A CAUSE OF SPATIAL STRUCTURE OF THEPROTEIN. SICKLE-CELL ANEMIA. AMYLOIDOSIS AND SERPINOPATHIES - DISEASES CAUSED BY CHANGES IN THE SPATIALSTRUCTURE OF THE PROTEIN AND ITS AGGREGATION. NEURODEGENERATIVE DISEASES OF A CHANGE IN THE SPATIAL STRUCTURE OF THEPROTEIN: HUNTINGTON'S CHOREA AND PARKINSON'S DISEASE. PRION PROTEIN. PRION DISEASES. PARKINSON'S DISEASE.Koval AN (C), 201924.09.20192

THE SUBJECT AND TASKS OF MEDICALBIOCHEMISTRY MEDICAL BIOCHEMISTRY –BIOCHEMISTRY WITH PARTICULARREFERENCE TO THE WAYS IN WHICHTHIS RELATES TO MEDICINE ANDHEALTH. MEDICAL BIOCHEMISTRY IS ABRANCH OF MEDICINE THATINCORPORATES BIOCHEMISTRYAND METABOLISM IN HUMAN ANDDISEASE. MEDICAL BIOCHEMISTRY IS A FIELDTHAT STUDIES DIFFERENT TYPES OFMOLECULES IN HOPES OFBETTERING TECHNOLOGY ANDMEDICINE.Koval AN (C), 2019https://study.com/articles/Medical Biochemistry Careers Job Options and Requirements.html24.09.20193

SOURCES: TEXTBOOKS MEDICAL BIOCHEMISTRY, 5TH EDITION,AUTHORS: JOHN BAYNES MAREK DOMINICZAK,2019, 712 PAGES PRINCIPLES OF MEDICAL BIOCHEMISTRY, 4THEDITION, AUTHORS: GERHARD MEISENBERG,WILLIAM H. SIMMONS,2017, 657 PAGESKoval AN (C), 201924.09.20194

SOURCES: WEB-PAGEHTTP://THEMEDICALBIOCHEMISTRYPAGE.ORG EASY ACCESSIBLE SITEFOR MEDICALSTUDENTS. AUTHOR: MICHAEL W.KING CONSTANTLY UPDATEDKoval AN (C), 201924.09.20195

GENERAL CHARACTERISTICS OF THE PROTEINBIOSYNTHESIS, PROCESSING, AND PROTEINFOLDING. PROTEINS PERFORM A VARIETY OF FUNCTIONS AND ENSURE THE EXISTENCE OF LIVING SYSTEMS. LINEAR CHAIN PROTEIN COMPOSED OF COVALENTLY LINKED 20 AMINO ACID SEQUENCE ENCODED BY THEGENETIC CODE. NUCLEOTIDE SEQUENCE DETERMINES THE ORDER OFAMINO ACIDS IN A PROTEIN, WITH ONE AMINOACID CORRESPONDS TO THE DNA SEQUENCE OFTHREE NUCLEOTIDES - CALLED A TRIPLET OR CODON.MOST AMINO ACIDS CAN BE CODED BY DIFFERENTTRIPLETS. THAT IS, THE GENETIC CODE CAN BE REDUNDANTOR OTHERWISE DEGENERATE. THE GENETIC CODEENCODING A DIFFERENT AMINO ACID HAVING ADIFFERENT DEGREE OF DEGENERACY (AMINO ACIDENCODED BY 1 TO 6 CODONS), IT DEPENDS ONTHE FREQUENCY OF OCCURRENCE OF THE AMINOACIDS IN PROTEINS.Koval AN (C), 201924.09.20196

PROTEIN’S LEVELS OF ORGANIZATIONFor the functioning of the protein molecules is important not only linear but also thespatial structure. For the formation of the latter, are linear chain protein molecules mustemerge into unique for each type of protein three-dimensional structures.Koval AN (C), 201924.09.20197

PROTEIN LIFE CYCLE CELLULAR COMPONENTS (PROTEINS, ORGANELLES) CAN BECOMEDAMAGED. THE CELL REQUIRES MECHANISMS TO REMOVE THE DAMAGEDMOLECULES TO ENSURE VIABILITY. THE PROCESSES OF PROTEINS AND ORGANELLES ARE DEGRADED,REMOVED AND RECYCLED ARE VITAL FOR CELLULAR SURVIVAL. HIGHLY SPECIFIC WAYS OF REGULATION. INCLUDE PROTEIN MODIFICATION, PROTEIN DEGRADATION AND AMINO ACID RECYCLING, ORGANELLE TAGGING, ENGULFMENT, AND LYSOSOMAL DEGRADATION WITH COMPONENT PARTS BEING RECYCLED.24.09.2019Koval AN (C), 20198

PROTEIN FOLDING THE PROCESS OF PROTEIN SYNTHESIS DOESNOT DIRECTLY RESULT IN THE GENERATIONOF FUNCTIONALLY AND STRUCTURALLYCOMPLETE MACROMOLECULES. MANY PROTEINS MUST UNDERGO ONE ORMORE FORMS OF MODIFICATION. THE FOLDING OF THE PROTEIN INTO ADEFINED THREE-DIMENSIONAL STRUCTURE. IN THE CELL NEWLY SYNTHESIZED PROTEINSARE AT GREAT RISK OF ABERRANT FOLDINGAND AGGREGATION CAN LEAD TO THEFORMATION OF POTENTIALLY TOXICSPECIES.Koval AN (C), 201924.09.20199

CHAPERONES TO REDUCE AND PREVENT THESE NEGATIVEOUTCOMES, CELLS HARBOR A COMPLEX NETWORKOF MOLECULAR CHAPERONES WHOSE FUNCTIONSARE TO PROMOTE EFFICIENT FOLDING AND TOPREVENT PROTEIN AGGREGATION. THE STRUCTURE OF PROTEINS WITHIN THE CELL IS INA HIGHLY DYNAMIC STATE AND, THEREFORE,CONSTANT MOLECULAR CHAPERONE SURVEILLANCEIS REQUIRED TO ENSURE PROTEIN HOMEOSTASISKoval AN (C), 201924.09.201910

ALL CHAPERONES CAN BE DIVIDED INTO SIXMAJOR GROUPS:1.HIGH MOLECULAR WEIGHT CHAPERONES, WITH A MOLECULAR WEIGHTOF FROM 100 TO 110 KDA;2.CHAPERONES-90 - WITH A MOLECULAR WEIGHT OF FROM 83 TO 90 KDA;3.CHAPERONES -70 - WITH A MOLECULAR WEIGHT OF 66 TO 78 KDA;4.CHAPERONES -60 - WITH A MOLECULAR WEIGHT OF ABOUT 60 KDA;5.CHAPERONES -40 - WITH A MOLECULAR WEIGHT OF ABOUT 40 KDA;6.LOW MOLECULAR WEIGHT CHAPERONES ABOUT 15 TO 30 KDA.Koval AN (C), 201924.09.201911

PROTEIN FOLDING SYSTEMKoval AN (C), 201924.09.201912

THE FOLDEX AND FOLDFX MODELS DEFININGTHE PROTEOSTASIS BOUNDARY(A)(B)ILLUSTRATED ARE THE INTERACTIVE PATHWAYS THATREQUIRE THE FRS TO EITHER COMPLETE THE FOLD FOREXPORT FROM THE ER (FOLDEX MODEL) {WISEMAN, 2007#616} OR FOR FUNCTION (FOLDFX MODEL) {POWERS, 2009#613}, OR CONTRIBUTE TO MISFOLDING, AGGREGATIONAND DEGRADATION THROUGH THE DRS. (B, C) ILLUSTRATEDIS THE PROTEOSTASIS BOUNDARY (PB) (INDICATED BY THEARROW) DEFINED BY KINETICS OF FOLDING (Z AXIS),KINETICS OF MISFOLDING (Y AXIS) AND THERMODYNAMICS(X AXIS) REFLECTING A TYPICAL CELLULAR COMPOSITION OFTHE PN (SEE {WISEMAN, 2007 #190} FOR DETAILS). THELOCATION OF A HYPOTHETICAL CELLULAR NETWORKFACILITATING CELL FUNCTION IS INDICATED BY THE GREENNODES AND EDGES, WHICH, IN A HEALTHY CELL (B) ISPROTECTED BY THE PN AND THEREFORE BENEATH THE PB. INDISEASE (C), A MUTATION CAN RESULT IN MISFOLDING (REDNODE AND EDGE) LEADING TO A LOSS-OF-FUNCTIONDISEASE, OR AGGREGATION (BLACK NODE AND EDGE)THAT CAN LEAD TO A GAIN-OF-TOXIC FUNCTION DISEASE.SEE {WISEMAN, 2007 #190}{POWERS, 2009 #613} FOR ATHOROUGH TREATMENT OF THE IMPACT OF MUTATION ONTHE PN LEADING TO HUMAN DISEASES. PANELS B AND CARE REPRODUCED WITH PERMISSION (ELSEVIER PRESS) IN AMODIFIED 805282/figure/F1/Koval AN (C), 201924.09.201913

COMPARTMENTALIZATION ANDPROTEOSTASIS BOUNDARIES Koval AN (C), 2019ILLUSTRATED IS AHYPOTHETICAL VIEW OFTHE DIFFERINGORGANIZATIONS OF THEPB FOUND IN THEINDICATEDCOMPARTMENTS. THEDIFFERENCES IN THESHAPE OF THE PBSREFLECT THE DIFFERENCESIN THE PN PRESENT INEACH OF THESECOMPARTMENTS OR INTHE EXTRACELLULARSPACE THAT PROMOTESFOLDING AND/ORMAINTENANCE OF THEFOLD.24.09.201914

AMYLOIDOSESA globular protein that has asomewhat flexible higher-orderstructure in its normal statespontaneously refolds into a statewith a high content of β-pleatedsheet.In some cases, stretches of α- helixrearrange into stretches of βpleated sheet. Unlike the α-helix,which is strictly intramolecular, theβ-pleated sheet can form extendedstructures that involve two or morepolypeptides.Koval AN (C), 2019These aggregatesresemble starch(amyloid).24.09.201915

AMYLOIDOSIS: SOME FORMSKoval AN (C), 201924.09.201916

AMYLOID IS NOT VERY TOXIC AND CAUSESNO IMMUNE RESPONSE, IT CAN DAMAGETHE ORGANS IN WHICH IT DEPOSITS TAU PROTEIN, WHICH STABILIZES THE MICROTUBULES IN THE AXONS OF NEURONS. ITS AFFINITY FOR MICROTUBULES IS REGULATED BY REVERSIBLE PHOSPHORYLATION ANDDEPHOSPHORYLATION OF SERINE AND THREONINE SIDE CHAINS. IN SEVERALNEURODEGENERATIVE DISEASES, INCLUDING ALZHEIMER DISEASE ANDFRONTOTEMPORAL DEMENTIA, EXCESSIVELY PHOSPHORYLATED(“HYPERPHOSPHORYLATED”) TAU PROTEIN FORMS FILAMENTOUS AGGREGATES IN THEAXONS, CAUSING THEIR EVENTUAL DEMISE. SOME PEOPLE ARE BORN WITH A STRUCTURALLY ABNORMAL TAU PROTEIN THAT IS MOREPRONE TO ABNORMAL PHOSPHORYLATION, DETACHES MORE EASILY FROM THEMICROTUBULES, OR IS MORE PRONE TO AGGREGATION AFTER IT HAS BEENPHOSPHORYLATED AND HAS DETACHED FROM THE MICROTUBULES. MOST OF THESEPATIENTS DEVELOP AN INHERITED FORM OF FRONTOTEMPORAL DEMENTIA WITHPARKINSONISM.Koval AN (C), 201924.09.201917

ALZHEIMER DISEASEΒ AMYLOID PROTEIN IS A MISFOLDED PROTEIN.IT FORMS FIBROUS DEPOSITS OR PLAQUES IN THE BRAINS OF ALZHEIMER’SPATIENTS.SYMPTOMS: MEMORY LOSS, DEMENTIA, IMPAIRMENT IN OTHER FORMS OFCOGNITION AND BEHAVIOR NOT TRANSMISSIBLE BETWEENINDIVIDUALS INTRACELLULAR AGGREGATES(FIBRILLAR TANGLES) OF PROTEINCALLED TAU EXTRACELLULAR PLAQUES CONTAINAGGREGATES OF Β-AMYLOIDPEPTIDES (AΒ):40-42-RESIDUESEGMENTS DERIVED BY PROTEOLYTICCLEAVAGE OF A MUCH LARGERPROTEIN (AMYLOID PRECURSORPROTEIN, APP) ATTACHED TOPLASMA MEMBRANE OF NEURONS(FUNCTION UNKNOWN)Koval AN (C), 201924.09.201918

B-AMYLOID PRECURSOR PROTEIN (ABB) ALPHA-Β IS FORMED BY THE PROTEOLYTIC CLEAVAGE OF Β-AMYLOID PRECURSOR PROTEIN(APP), A MEMBRANE PROTEIN THAT TRAVERSES THE LIPID BILAYER OF THE PLASMAMEMBRANE BY MEANS OF AN Α-HELIX. AFTER AN INITIAL CLEAVAGE THAT IS CATALYZED BY THE PROTEASE Β-SECRETASE, ANOTHERPROTEASE CALLED Γ-SECRETASE CLEAVES THE REMAINING POLYPEPTIDE WITHIN THE LIPID BILAYEROF THE PLASMA MEMBRANE, CREATING AN INTRACELLULAR FRAGMENT AND THE EXTRACELLULARAΒ. Γ-SECRETASE CLEAVAGE IS IMPRECISE, AND EXTRACELLULAR POLYPEPTIDES OF 40 AND 42AMINO ACIDS CAN BE FORMED. LESS THAN 10% OF THE PRODUCT IS AΒ-42, BUT THIS FORM IS FAR MOREAMYLOIDOGENIC THAN AΒ-40. IT FOLDS INTO A FORM THAT CONTAINS A PARALLEL Β-PLEATED SHEET WITH TWOSTRETCHES OF 10 TO 12 AMINO ACIDS EACH. THIS STRUCTURE POLYMERIZES INTO AMYLOID FIBRILS, FORMING THE SENILE PLAQUES.Koval AN (C), 201924.09.201919

ALPHA-SYNUCLEIN ANOTHER PROBLEM PROTEIN IS Α-SYNUCLEIN, A SMALL (140 AMINO ACIDS), UNSTABLYFOLDED, MEMBRANE-ASSOCIATED INTRACELLULAR PROTEIN THAT CAN AGGREGATE INTOCYTOPLASMIC GRANULES CALLED LEWY BODIES. MOST PATIENTS WITH PARKINSON DISEASE HAVE LEWY BODIES IN THEIR AILINGDOPAMINE NEURONS. PARKINSON DISEASE IS A MOTOR DISORDER MANIFESTED AS TREMOR, RIGOR, ANDAKINESIA. IT IS THE SECOND MOST COMMON NEURODEGENERATIVE DISEASE AFTER ALZHEIMERDISEASE, AFFECTING 1% TO 3% OF PEOPLE OLDER THAN 65 YEARS. PEOPLE WHO ARE BORN WITH STRUCTURALLY ABNORMAL VARIANTS OF Α-SYNUCLEIN ORWHO OVERPRODUCE STRUCTURALLY NORMAL Α-SYNUCLEIN AS A RESULT OF GENEDUPLICATION OR TRIPLICATION CAN DEVELOP EARLY-ONSET FORMS OF PARKINSONDISEASE. WIDESPREAD DEPOSITS OF Α-SYNUCLEIN IN THE BRAIN ARE FOUND IN SOME DEMENTEDPATIENTS, AND SOME PARKINSON DISEASE PATIENTS BECOME DEMENTED WHEN NEURONSOTHER THAN THE DOPAMINE NEURONS OF THE SUBSTANTIA NIGRA BECOME INVOLVED INTHE DISEASE.Koval AN (C), 201924.09.201920

PARKINSON DISEASE OTHER DISEASES INVOLVING ABNORMALFOLDING/AGGREGATION OF OTHER PROTEINS PARKINSON DISEASE – PROTEIN THAT FORMS FIBRILS IS Α-SYNUCLEIN. – LESIONS ("LEWY BODIES") FORM IN CYTOSOL OF DOPAMINERGICNEURONS IN SUBSTANTIA NEGRA OF BRAIN, ACCOMPANIED BYMUSCLE RIGIDITY AND RESTING TREMOR.Koval AN (C), 201924.09.201921

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MISFOLDED PROTEIN CAN BECONTAGIOUS AN UNUSUAL TYPE OF NEURODEGENERATION IS CAUSED BYAGGREGATES OF THE PRION PROTEIN (PRP). THE NORMAL CELLULARPRION PROTEIN (PRPC) IS AN ABUNDANT PROTEIN IN THE NERVOUSSYSTEM, WHERE IT IS TETHERED TO THE SURFACE OF NEURONS BY ACOVALENTLY BOUND GLYCOSYLPHOSPHATIDYLINOSITOL ANCHORTHAT IS INSERTED INTO THE LIPID BILAYER OF THE PLASMA MEMBRANE.SMALLER AMOUNTS ARE PRESENT IN OTHER ORGANS, IN BLOOD,AND CEREBROSPINAL FLUID.Koval AN (C), 201924.09.201923

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CREUTZFELDT-JAKOB DISEASE (CJD) CREUTZFELDT-JAKOB DISEASE (CJD) IS A RARE DISEASE (INCIDENCE ONEPER MILLION PER YEAR) OF MIDDLE-AGED AND OLD PEOPLE IN WHOMMENTAL DETERIORATION PROGRESSES TO DEATH WITHIN WEEKS ORMONTHS. AT AUTOPSY THE BRAIN IS FOUND TO BE RIDDLED WITH HOLES THAT MAKEIT LOOK LIKE SWISS CHEESE OR A SPONGE; THEREFORE, THIS TYPE OFDISEASE IS CHARACTERIZED AS A SPONGIFORM ENCEPHALOPATHY.Koval AN (C), 201924.09.201925