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HEMOGLOBIN AND MYOGLOBIN: NEW PROPERTIES FROM QUATERNARY STRUCTURE Physiological functions • Myoglobin stores oxygen in muscles. It releases oxygen only when oxygen concentration is very low (hypoxia) • Hemoglobin transfers oxygen from lungs to tissues. It releases oxygen when oxygen concentration is in physiological range. О2 is bound to heme group Oxygen saturation curves for myoglobin (hyperbolic) and hemoglobin (sigmoidal): different ability to transfer oxygen Lungs: both proteins are saturated with oxygen. Tissues: - myoglobin is 90% saturated (gives back only 10%) - hemoglobin is 50% saturated (gives back 50%) QUATERNARY STRUCTURE MATTERS Myoglobin consists of single polypeptide chain, while functional hemoglobin molecule contains four polypeptide chains (which are very similar to myoglobin ones) Myoglobin (single chain) Hemoglobin (one subunit) Hemoglobin (four subunits) Binding of oxygen molecule by the first subunit enhances oxygen binding to other subunits This feature is called cooperativity THE CAUSE OF COOPERATIVITY Subunits interact with each other Interaction in more details Oxygen binding leads to structural (conformational) changes in binding site, which are transmitted to neighboring subunits through contacts between subunits Binding of oxygen molecule by the first subunit enhances oxygen binding to other subunits Structure determines ability for oxygen binding Conformational (structural) changes in hemoglobin molecule after oxygen binding Summary • Binding of the first oxygen molecule changes structure of neighboring subunits • These changes enhance oxygen binding Hemoglobin: physiological regulation 2,3-BISPHOSPHOGLYCERATE AND COOPERATIVITY 2,3-BPG is produced from one of the glycolysis intermediates The presence of 2,3BPG indicates sites of high energy production and, therefore, oxygen demand 2,3-BPG binds to the central cavity of hemoglobin molecule Effects of 2,3-BPG: • 2,3-BPG weakens oxygen binding. Therefore: • High 2,3-BPG in tissue → weak oxygen binding → better oxygen supply This plays role in adaptation to highlands and intensive work CLINICAL POINTS: BINDING OF CO CO binding disturbs cooperativity of oxygen binding HEMOGLOBIN ISOFORMS: - ADULT - FETAL Synthesis of different isoforms during embryonic development Fetal vs. adult hemoglobin PHYSIOLOGICAL REGULATION OF OXYGEN BINDING: EFFECTS OF PH AND CO2 Effects of pH and CO2 Tissues with high energy demand (high glycolysis): - high CO2 -low pH Summary • Proteins with quaternary structure may display cooperative binding • Cooperativity is caused by conformational changes in the first protein subunit which lead to conformational and binding rate changes in neighboring subunits • Regulatory molecules usually change conformation and therefore properties of protein • This is the basis of physiological regulation of protein activity • In hemoglobin oxygen binding is regulated by 2,3-BPG, CO2 and pH • Different protein isoforms are differently regulated NUCLEIC ACIDS DNA and RNA contain nitrogen bases Nucleotides vs. nucleosides How is this nucleoside / nucleotide called? There are some other nitrogen bases • Alkaloids • Products of nitrogen bases breakdown Some bases are not included in nucleic acids structure: alkaloids H caffeine H theophilline theobromine Nitrogen bases which are formed during metabolism from adenine and guanine hypoxanthine xanthine Uric acid Elevation of uric acid causes gout • Uric acid forms insoluble salts • Causes: increased production OR decreased excretion DNA contains minor (modified) bases: regulation of gene expression by methylation RNA contains minor bases: recognition, stability, regulation mRNA tRNA FUNCTIONS ATP as energy carrier high energy bond (macroergic bond, high energy phosphate) = good leaving group, high transfer potential (correct meaning) Nucleotide moieties of coenzymes: coenzyme A Nucleotide moieties of coenzymes: NAD Nucleotide moieties of coenzymes: FAD Regulatory functions of cyclic nucleotides cAMP has positive effect on energy-production pathways (glycolysis). One of the mechanisms of caffeine action is inhibition of cAMP breakdown. This leads to prolongation of cAMP stimulatory action. cGMP mediates muscle relaxation caused by NO. Effect of nitroglycerin on heart muscle relaxation is mediated by cGMP formation. Summary • Nucleotides consist of nitrogen base (A,T,G,C,U) + (deoxy)ribose + phosphate • Nucleotides are the building blocks of nucleic acids (DNA, RNA) • Nucleotides perform signaling functions (cAMP, cGMP) • Nucleotides play role in catalysis (parts of coenzymes). • Nucleotides are energy carriers (ATP, GTP) NUCLEIC ACIDS: DNA Nucleotides (in DNA or RNA) are joined by phosphodiester bonds Conventional order of sequence description is from 5`- to 3`- end: 5` ATG 3` DNA is a double helix DNA STRUCTURE AND DRUGS Intercalation – insertion between planar bases of double helix Intercalating drugs: bacteriostatics proflavin Intercalating drugs for cancer cisplatin Mechanism of intercalation NUCLEIC ACIDS: RNA Differences between RNA and DNA: pentose Lack of OH-group makes DNA more chemically stable: DNA is more suitable for storing genetic information RNA functions in protein synthesis: ribosomal RNA perform catalytic functions RNA is the major structural component of ribosomal subunits 30S rRNA (brown) + proteins (blue): rRNA: 50S RNA functions in protein synthesis: transfer RNA (tRNA) Real conformation in 3D RNA functions in protein synthesis: messenger RNA (mRNA) Other functions of RNA: • Catalysis (ribozymes): ribosome, RNAse P, hammerhead ribozyme. • Regulation of gene expression (RNA interference): small interfering RNAs RNA as catalyst: ribozymes RNase P plays role in: - tRNA processing - regulation of transcription