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Metabolisme Protein Saryono Bagian Biokimia
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  • Metabolisme Protein SaryonoBagian Biokimia

  • Protein1. Large molecules, 103 to 108amu2. Polymers of amino acids in specific sequences3. Sequence determines function4. Homo sapiens, 20 different amino acids make up all proteins

  • Asam amino dan proteinAsam amino terdiri dari gugus karboksilat dan gugus aminoProtein tdr dari beberapa asam amino yang terikat dengan ikatan peptide.Ikatan peptida adalah ikatan yang menghubungkan gugus amin dari suatu asam amino dengan gugus karboksilat dari senyawa asam amino yang lain

  • Asam amino sebagai ion dipolarKarena mengandung gugus karboksilat dan gugus amino, maka dapat bersifat zwitter ion (bermuatan +/-)Walaupun netral, tetapi ion dipolar masih merupakan senyawa ionSifat fisik: titik didih tinggi, dapat larut dalam air, tetapi tidak larut dalam pelarut organikIon dipolar bersifat amfoter, dapat bereaksi dengan asam/basa

  • Berdasarkan rantai sampingAsam amino netral:alanin, glisin, isoleusin, leusin, metionin, fenilalanin, prolin, triptofan, valinAsam amino polar+nonpolarAsam amino basa: arginin, lisin dan histidinAsam amino asam: asam aspartat dan asam glutamat

  • Asam aminoSemua asam amino kecuali glisin, pada atom C-2 terikat 4 gugus yang berbeda: gugus karboksilat, gugus amino, atom H dan rantai samping RAA alifatik: Gly, Ala, Val, Leu, IleAA mengandung S: Cys, MetAA mengandung gugus OH: Ser, Thr, TryAA mengandung gugus asam : Asp, Asn, Glu, GlnAA mengandung cincin aromatik : His, Phe, Tyr, TrpAA mengandung gugus basa: Arg, Lys, HisAA imino: Pro

  • Protein Types1. Structural- provide structurea. Collagen- tendons & cartilageb. Keratin- hair, skin, wool, & nailsc. Spongin- sponges, Porifera2. Contractile- movement, muscles & filamentsa. Myosin- contractile ms filamentb. Actin- anchor ms filament

  • Protein Types3. Transport- carry substances in bodya. Hemoglobin & hemocyan- transport O2b. Lipoproteins- transport lipids4. Storage- store nutrientsa. Casein- stores protein in milkb. Albumin- stores protein in eggs & bloodc. Ferritin-stores iron in spleen & liver

  • Protein Types5. Hormone- regulate metabolism & nervous systema. Insulin- regulates blood glucose levelsb. Somatropin- growth hormone, regulates growth phases

  • Protein Types6. Enzyme- catalyse biochem rxna. Sucrase- hydrolysis of sucroseb. Trypsin- hydrolysis of proteins7. Protection- defense of organisma. Immunoglobulins- stimulate immune responseb. Venoms- poisons to kill, stun, or discourage attackers

  • Enzymes1. Protein catalysts that lower activation energy & # rxn rate of cellular chemical reactions required for metabolism2. Pepsin, trypsine, sucrase, lipases, carbonic anhydrase

  • Amino Acids1. H atom, amino group, carboxyl group, & functional group attached to central carbon, aC2. Different functional groups determine characteristics of individual amino acids3. Nonpolar aa, polar aa, acidic aa, basic aa

  • Non-Essential Amino Acids in Humans Not required in diet Can be formed from a-keto acids by transamination and subsequent reactions Alanine Asparagine Aspartate Glutamate Glutamine Glycine Proline Serine Cysteine (from Met*) Tyrosine (from Phe*)* Essential amino acids

  • Essential Amino Acids in Humans Required in diet Humans incapable of forming requisite carbon skeleton Arginine* Histidine* Isoleucine Leucine Valine Lysine Methionine Threonine Phenylalanine Tryptophan* Essential in children, not in adults

  • Amino Acid Structure

    amino carboxyl group group

    functional group

  • Nonpolar Amino Acids1. Hydrophobic aromatic group or hydrocarbon chain2. Glycine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan

  • Polar Amino Acids1. Hydrophilic functional groups2. Serine, threonine, asparagine, cysteine, tyrosine, glutamine

  • Acidic Amino Acids1. Carboxylic acid on functional group2. Aspartic acid, glutamic acid

  • Basic Amino Acids1. Amine group on functional group2. Lysine, arginine, histidine

  • Essential Amino Acids1. Ten aa are essential, must be in diet2. Essential- arg, his, ile, leu, lys, met, phe, thr, trp, val3. Ten aa can be synthesized from essentials4. Nonessential- ala, asn, asp, cys, gln, glu, gly, pro, ser, tyr

  • Dipolar IonDipolar ion- carboxyl group donates H+ and amino grp accepts H+

    alanine, dipolar ion

  • Amino Acid Ionization1. Most aa exist as dipolar ions, net charge = 02. In acid soln, carboxyl grp accepts H+ & aa has positive charge3. In basic soln, amino grp donates H+ & aa has negative charge

  • Peptide bond1. Amide bond between carboxyl grp of one aa & amino grp of another2. Small peptides named starting at amino group using -yl or 3 letter abbreviations

  • Tripeptidealanylglycylserine or ala-gly-ser, a tripeptide

  • AspartameL-aspartic acid & methylesterphenylalanine

  • Polypeptide1. Long chains of amino acids2. Protein- >50 amino acids3. Primary, secondary, tertiary, & quaternary structure

  • Struktur proteinStruktur primer;urutan/order AA dalam rantai proteinStruktur sekunder;Alfa heliks;tulang punggung terpilin membentuk coil/ulirBeta pleated sheet; lembaran terlipat betaParalelAntiparalel Ikatan hidrogen, interaksi hidrofob, interaksi elektrostatik, interaksi van der waalsStruktur tersier; lipatan/gulungan yang kompleksIkatan disulfida memberikan stabilitas tambahanStruktur kwaterner; persekutuan unit protein

  • Primary Structure, 1o1. Sequence of amino acids in protein, 1o sequence determines function2. Thyroxine Releasing Hormone- glu-his-pro sequence3. Insulin- two chains, 21 aa in a chain & 30 aa in b chain

  • Secondary Structure1. Alpha helix2. Beta plate sheet3. Triple helix

  • Alpha Helix1. Hydrogen bonds between amino groups & carbonyl groups twist amino acid chain into a helix or spiral2. Functional groups are outside

  • Beta Sheet1. Hydrogen bonds between amino groups & carbonyl groups fold parallel amino acid chains into pleated sheet2. Functional groups are on opposite sides of sheet

  • Triple Helix1. Three amino acid chains woven into a braid2. Structure of collagen, found in connective tissue, skin, tendons, ligaments

  • Tertiary1. Three dimensional shape of protein2. Attractions & repulsions from side groups fold protein into specific shape3. Globular proteins- compact & roughly spherical, polar4. Fibrous proteins- long & thin fibers, structural

  • Quaternary1. Two or more polypeptide units held together by side group interaction2. Hemoglobin- globular, two a chains & two b chains

  • Protein Denaturation1. Bonds that stabilize the 2o, 3o, or 4o structure weakened or broken2. Heat, acids, bases, certain organic compounds, heavy metal ions, & agitation

  • Amino Acid BiosynthesisPlants and microorganisms can make all 20 amino acids and all other organisms need N metabolites In these organisms, glutamate is the source of N, via transamination (aminotransferase) reactions Mammals can make only 10 of the 20 amino acids The others are classed as "essential" amino acids and must be obtained in the diet All amino acids are grouped into families according to the intermediates that they are made from

  • Biosintesis asam aminoVertebra tidak dapat melakukan biosintesis asam amino essensialHanya non essensial yang dapat disintesis dari senyawa antara amfibolik lewat lintasan metabolikSenyawa antara : siklus asam sitrat, alfa ketoglutarat (Glu, Gln, Pro, Hyp), oksaloasetat (Asp, Asn), serta senyawa bersifat glikolitik, 3-fosfogliserat (Ser, Gly)Ketiga AA lainnya (Cys, Tyr, Hyl) dibentuk dari asam amino essensial

  • Glutamate-dependent transamination - primary mechanism for amino acid synthesis

  • Asam amino esensialDiabsorpsi melalui:Transport tergantung Na+Difusi terfasilitasiTransport terikat pada -glutamyl cycle

  • Transport tergantung Na+Na+ di dalam sel intestinal rendah o/k dipompa keluar ke sisi serosa oleh pompa Na,K,ATPaseNa+ dan asam amino dipompa masuk ke sel dari lumen intestinalAA dibawa dengan transporter terfasilitasi di dalam membran serosa ke darah

  • -glutamyl cycleDi dalam ginjal dan intestinalAA ekstrasel berreaksi dengan glutation---menjadi -glutamyl AA-glutamyl AA melewati membran sel dan melepaskan AA ke dalam selProduk lain dikonversi kembali menjadi glutation

  • Protein metabolism8/9 Essential amino acids: must eat them!Transamination: use the essential AA to synthesize the others!

  • Protein metabolismAnother route:Intestinal bacteria -> ammonia (toxic) -> liver uses it to make amino acids

  • Protein metabolismAmino acids: C, H, O plus amine group with N

    Healthy adult: ingest N=excrete N (turnover of proteins!)

  • Protein metabolismAmino acids are broken down into:a) ammonia -> ureab) pyruvate or molecules that are part of the krebs cycle -> respired for energy, or converted to fats or glucose

  • Glucogenic Amino AcidsMetabolized to a-ketoglutarate, pyruvate, oxaloacetate, fumarate, or succinyl CoA Aspartate Asparagine Arginine Phenylalanine Tyrosine Isoleucine Methionine Valine Glutamine Glutamate Proline Histidine Alanine Serine Cysteine Glycine Threonine Tryptophan

  • Ketogenic Amino AcidsMetabolized to acetyl CoA or acetoacetate Isoleucine Leucine Threonine Tryptophan Lysine Phenylalanine Tyrosine

  • Katabolisme kerangka karbon pada asam aminoKalau AA tdp melebihi kebutuhan metabolik, kerangka karbonnya akan dikatabolisasi menjadi senyawa antara sebagai sumber energi, atau sebagai substrat bagi sintesis KH, lipidGlikogenik: Ala, Arg, Asp, Cys, Glu, Gly, His, Hyp, Met, Pro, Ser, Thr, ValKetogenik: LeuGlikogenik dan ketogenik: Ile, Lys, Phe, Trp, Tyr

  • Keseimbangan nitrogenMengacu pada perbedaan asupan total nitrogen dengan kehilangan nitrogen melalui feses, urin, keringatKeseimbangan nitrogen positif: konsumsi nitrogen dengan jumlah yang lebih banyak drpd jumlah yang diekskresikanProtein diuraikan dengan kecepatan yang berbeda-bedaBinatang mengekskresikan nitrogen sebagai hasil akhirnya berupa amonia, asam urat atau urea

  • Siklus ureaUrea merupakan produk akhir katabolisme nitrogen pada manusia, disintesis dari amonia, CO2, dan nitrogen amida aspartatKarena sintesis urea mengubah amonia yang toksik menjadi urea yang non toksik, semua defek pada sintesis urea akan mengakibatkan intoksikasi amonia.

  • Kelainan pada siklus ureaGejala klinis: mual, muntah terhadap makanan berprotein tinggi, iritabilitas, letargia, retardasi mental. Kelainan berupa : hiperamonemia, sitrulinemia, hiperargininemia, arginosuksinikasiduria

  • Defisiensi asam aminoDef. asam amino essensial Kwashiorkor: kadar protein plasma rendah, edema, diare, peningkatan resiko infeksiMarasmus : kekurangan kalori dan protein

  • Amino Acids Formed From a-KetoglutarateTransamination or Glutamate dehydrogenasea-Keto-glutarateGlutamateGlutamineGlutamine synthase4 StepsProlineOrnithine5 StepsArginineUrea CycleGuanidino group

  • GABA FormationGlutamateGamma-aminobutyrate(GABA)GABA is an important inhibitory neurotransmitterin the brainDrugs (e.g., benzodiazepines) that enhance the effectsof GABA are useful in treating epilepsy GlutamatedecarboxylaseCO2

  • Arginine Synthesis: The Urea CycleNH4+ + HCO3- NH2CO2PO3-2GlutamateN-AcetylglutamateOrnithineN-AcetylglutamatesynthaseCoASAc4 StepsCPS-IOrnithine Transcarbamoylase (OTC)(mitochondria)CitrullineUreido groupCarbamoyl phosphateActivates

  • The Urea Cycle (Contd.)CitrullineArginosuccinateArginosuccinatesynthaseArginineOrnithineFumarateTCA CycleArginaseH2NCONH2UreaArgino-succinaseOrnithineTranscarbamoylase(mitochondria)Asp

  • Urea FormationOccurs primarily in liver; excreted by kidneyPrincipal method for removing ammoniaHyperammonemia:Defects in urea cycle enzymes (CPS, OTC, etc.)Severe neurological defects in neonatesTreatment: Stop protein intakeDialysisIncrease ammonia excretion: Na benzoate, Na phenylbutyrate, L-arginine, L-citrulline

  • Blood Urea NitrogenNormal range: 7-18 mg./dLElevated in amino acid catabolism Glutamate N-acetylglutamate CPS-1 activationElevated in renal insufficiencyDecreased in hepatic failure

  • Formation of SerineGlucoseGlycolysis3-Phospho-glycerate3-Phospho-hydroxypyruvate3-PhosphoserineSerine (Ser)PyruvateDehydrogenaseNAD+ NADH + H+Glutamatea-KetoglutarateTransaminasePhosphatase3 StepsInhibits

  • Conversion of Serine to GlycineFolateTetrahydrofolate (FH4)Dihydrofolate reductaseN5, N10-Methylene FH4SerineGlycineSerine hydroxymethyltransferase (PLP-dep.)Key intermediatein biosynthesis ofpurines andformation ofthymineImportant in biosynthesis of heme,porphyrins, and purines

  • Sulfur-Containing Amino AcidsMethionine(Essential)L-HomocysteineMethionineSynthase(Vit. B12-dep.)+ FH4+ 5-Methyl FH4SerineCystathionineCystathionineb-synthase(PLP-dep.)CystathioninelyaseCysteine(Non-essential)+b-Hydroxy-butyrate

  • HomocysteineHomocysteinuria Rare; deficiency of cystathionine b-synthase Dislocated optical lenses Mental retardation Osteoporosis Cardiovascular disease death

    High blood levels of homocysteine associated withcardiovascular disease May be related to dietary folate deficiency Folate enhances conversion of homocysteine to methionine

  • Methionine Metabolism: Methyl DonationS-Adenosyl methioninesynthaseATPS-Adenosyl Methionine(SAM)S-Adenosyl homocysteineMethyl-transferasesDecarboxylated SAMSAM DecarboxylaseCO2MethionineR-HR-CH3+

  • Polyamine BiosynthesisOrnithine(from urea cycle)PutrescineCO2Ornithinedecarboxylase(ODC)(PLP-dep.)DecarboxylatedSAMSpermidine synthase5-Methylthio-adenosineSpermidineSpermineDecarboxylatedSAMSpermine synthase5-Methylthio-adenosine

  • Polyamines Spermidine and spermine found in virtually all procaryotic and eucaryotic cells

    Precise role undefined Bind to nucleic acids

    Inhibition of biosynthetic pathway:a-Difluoromethyl-ornithine (DFMO)(Eflornithine) - inhibits ODC;used to treatPneumocystis carinii infectons

  • Creatine and CreatinineArginineGlycine OrnithineArginine-glycinetransamidinase(Kidney)GuanidoacetateGuanidoacetateMethyltransferase(Liver)SAM + ATP

    S-Adenosyl-homocysteine + ADPPhosphocreatineCreatinine(Urine)Non-enzymatic(Muscle)Creatine kinase(Muscle)ATPCreatineADP + Pi

  • Creatine and Creatinine Creatine: Dietary supplement Used to improve athletic performance

    Creatinine: Urinary excretion generally constant; proportional to muscle mass

    Creatinine Clearance Test: Compares the level of creatinine in urine (24 hrs.) with the creatinine level in the blood Used to assess kidney function Important determinant in dosing of several drugs in patients with impaired renal function

  • Histidine Metabolism: Histamine FormationHistidineHistamineHistidinedecarboxylaseCO2Histamine: Synthesized in and released by mast cells Mediator of allergic response: vasodilation, bronchoconstriction (H1 receptors) H1 blockers: Diphenhydramine (Benadryl) Loratidine (Claritin) Stimulates secretion of gastric acid (H2 receptors) H2 blockers: Cimetidine (Tagamet); ranitidine (Zantac)

  • Phenylalanine and TyrosinePhenylalanine(Essential)Tyrosine(Non-essential)Phenylalanine-4-Monooxygenase(Phenylalaninehydroxylase)O2H2O++NADPH + H+NADP+TetrahydrobiopterinDihydrobiopterin

  • Phenylketonuria (PKU) DiseaseDeficiency of Phe hydroxylaseOccurs in 1:16,000 live births in U.S.Seizures, mental retardation, brain damageTreatment: limit phenylalanine intakeScreening of all newborns mandated in all statesPheTyrTransaminationPhenylpyruvate(urine)

  • Catecholamine BiosynthesisTyr hydroxylaseO2TyrosineDihydroxyphenylalanine (DOPA)DopamineDOPAdecarboxylaseCO2DopaminehydroxylaseNorepinephrineCatecholEpinephrine(Adrenaline)SAMS-Adenosyl-homocysteineMethyl transferaseDOPA, dopamine, norepinephrine,and epinephrine are all neurotransmitters

  • L-DOPA in ParkinsonismBlood BrainBloodBrain BarrierL-DOPAL-DOPA DopamineDopamineCarbidopaBlocksParkinsonism associated with dopamine in brain through loss ofneurons in basal ganglia.Carbidopa + L-DOPA

  • Melanin FormationHighly colored polymeric intermediatesMelanin(Black polymer)TyrosinaseDOPADopaquinoneTyrosineTyrosinaseMelanin formed in skin (melanocytes), eyes, and hairIn skin, protects against sunlightAlbinism: genetic deficiency of tyrosinase

  • Tryptophan Metabolism: Serotonin FormationTryptophan(Trp)Indole ringTrphydroxylaseO25-Hydroxy-tryptophanDecarboxylaseCO25-Hydroxy-tryptamine (5-HT);Serotonin

  • Serotonin Serotonin formed in: Brain (neurotransmitter; regulation of sleep, mood, appetite) Platelets (platelet aggregation, vasoconstriction) Smooth muscle (contraction) Gastrointestinal tract (enterochromaffin cells - major storage site)

    Drugs affecting serotonin actions used to treat: DepressionSerotonin-selective reuptake inhibitors (SSRI) Migraine Schizophrenia Obsessive-compulsive disorders Chemotherapy-induced emesis

    Some hallucinogens (e.g., LSD) act as serotonin agonists

  • Food supplement promoted for serotonin effects L-Tryptophan disaster (1989): Eosinophilia-myalgia syndrome (EMS) Severe muscle and joint pain Weakness Swelling of the arms and legs Fever Skin rash Eosinophilia Many hundreds of cases; several deaths Traced to impurities L-Tryptophan

  • Serotonin Metabolism: 5-HIAASerotoninMAODehydrogenase5-Hydroxyindole acetic acid (5-HIAA) (Urine)Carcinoid tumors: Malignant GI tumor type Excretion of large amounts of 5-HIAA

  • Serotonin Metabolism: Melatonin2 StepsSerotoninMelatoninMelatonin: Formed principally in pineal gland Synthesis controlled by light, among other factors Induces skin lightening Suppresses ovarian function Possible use in sleep disorders

  • Tryptophan Metabolism:Biosynthesis of Nicotinic AcidTryptophanNicotinic acid (Niacin)Several stepsNicotinamide adenine dinucleotide (NAD)

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