Biochemistry 301 Week 6 Notes
Biochemistry 301 Week 6 Notes BBMB 301
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This 9 page Class Notes was uploaded by Emily on Wednesday February 17, 2016. The Class Notes belongs to BBMB 301 at Iowa State University taught by Robert Thornburg in Spring 2016. Since its upload, it has received 22 views. For similar materials see Survey of Biochemistry in General Science at Iowa State University.
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Date Created: 02/17/16
Biochemistry 301 – Survey of Biochemistry Professor Robert Thornburg LECTURE 14 – CHAPTER 14 – Entry into Metabolism By: Emily Settle Catabolism Stage 1: polymeric biomolecules first hydrolyzed into building blocks o Proteins to amino acids o Polysaccharides to monosaccharides o Triacylglycerols to fatty acids o Building block molecules enter blood stream to supply tissues around the body Protein Conversion to Amino Acids o Proteins first denatured from folded to unfolded state Stomach pH = 1-2 Why do acid conditions denature proteins? Acidic conditions disrupt α-helices and β-sheets leading to uncoiled, randomly shaped molecules. Why is the stomach so acidic? Acidic conditions kill bacteria that are ingested into the body while eating. Where does stomach acid come from? Gastric acid is produced by the parietal cells which contain high concentrations of a transport protein called the hydrogen/potassium ATPase. This protein pumps hydrogen outside the cell and takes potassium up into the cell at the cost of 1 ATP How does the stomach protect itself from digestion? The epithelial cells of the stomach secrete both mucins that coat the stomach’s surface with a thick slime and high levels of sodium bicarbonate to neutralize the stomach’s acid before it contacts the stomach’s lining cell layers Protein Conversion to Amino Acids o Proteases hydrolyze peptide bonds Pepsin is synthesized by the stomach’s parietal cells Pepsin is first, generates oligopeptide fragments of protein Pepsin is unusual because it retains activity at pH 1-2 o Partially digested protein moves to small intestine Oligopeptides and acid conditions signal the cells in the duodenum that digestion is beginning. The duodenal cells secrete the hormones secretin and cholecystokinin (CCK) Secretin signals to the pancreas to secrete more proteases into intestine Secreted proteases are released in an inactive form zymogen form Activation of Proteases – Zymogen Cascade o Zymogen – inactive form of an enzyme that is activated by proteolytic cleavage o Proteases are kept inactive until needed To avoid digestion of native proteins within the pancreas Avoid digestion of pancreas Completion of Protein Digestion o Final products of first stage of protein digestion are amino acids, dipeptides, and tripeptides o Peptidases are located on exterior surface of intestinal epithelial cells lining the intestine Hydrolyze peptide bonds Specific for small oligopeptides, so they don’t damage proteins o Amino acids, di-, tri-peptides transported into intestinal epithelial cells Facilitated transport proteins, many different ones Further hydrolysis inside cells More transporters move amino acids to capillaries and then further into blood stream Carbohydrate Digestion – Formation of Monosaccharides o A suite of hydrolase enzymes cleave O-glycoside bonds Some in saliva Most secreted by pancreas into small intestine Different specificities Α(14), α(16), or both o Monosaccharides move into intestinal epithelia then into blood stream Secondary active transport coupled to Na+ gradient ATP hydrolysis investment needed to get the fuel to the tissues where it will be used to generate a net gain of ATP Lipid Digestion o Lipids are first broken down to fatty acids, then transported, then reassembled into triacylglycerol, then transported again, then broken down to FAs again, then used as fuel o Triacylglycerol hydrolyzed in stomach to form FAs Lipases secreted by pancreas release FAs Pancreas supplies enzymes to both the intestine and the stomach Move to intestine, emulsified into lipid droplets Bile salts are steroids secreted by gall bladder that act as detergents to emulsify dietary fats FAs cross membrane into intestinal epithelial cells o TAGs reassembled in intestinal cells o TAGs are transported through the circulatory system These are packaged into particles with proteins on the outside that have hydrophilic surfaces Particles are secreted into lymph system, then move into blood stream Lipid Digestion o Reactions in stomach Triacylglycerol Diacylglycerol Monocylglycerol o Reactions in intestinal mucosal cells o Fatty acids are transported to target tissues o Proteins bind to receptors on target tissues Muscle, adipocytes These receptors are lipoprotein lipases, which hydrolyze triacylglycerol to glycerol plus free FAs Lipoproteins o Remnant “empty” chylomicrons are used again in the liver to synthesize other triacylglycerl/cholesterol transport particles o 5 types Chylomicrons: distribute dietary lipids to cells via lymph system VLDL (very low density lipoprotein): distributes endogenous (newly synthesized) lipids to cells IDL (intermediate density lipoprotein): cleared by liver and formed into LDL (BAD) LDL (low density lipoprotein): risk of cardiovascular disease (GOOD) HDL (high density lipoprotein): transfers lipids to liver, adrenal glands, ovary, testes for degradation or reprocessing Biochemistry 301 – Survey of Biochemistry Professor Robert Thornburg LECTURE 15 – CHAPTER 15 – INTRODUCTION TO METABOLISM By: Emily Settle Overview of Metabolism o Intermediary metabolism Collection of sets of ordered chemical reactions Extract storable chemical energy from energy rich compounds High energy compounds have lots of highly reduced carbon Carbon is oxidized, releasing chemical energy, which is captured in a storable form Use stored chemical energy to build biopolymers for growth and maintenance of the system Oxidized carbon is reduced as biopolymers are assembled o Catabolism Oxidation of carbon Breakdown of large molecules to small ones, release of energy o Anabolism Reduction of carbon Assembly of large molecules from small building blocks, consumption of energy Energy Conversation in Biological Systems o First law of thermodynamics Energy is constant in system plus surroundings o Enthalpy change ΔH: Heat released or absorbed for a chemical reaction At constant volume and pressure No work done o ΔH converts chemical bond energy into heat Negative ΔH: heat released – exothermic – releases energy Positive ΔH: heat absorbed – endothermic – requires input of energy o Both exo and endo can occur spontaneously ΔH by itself does not determine direction of a reaction Coupled Reaction o A reaction that results in positive ΔG can be made to run forward by coupling it with another reaction that has a negative ΔG The total ΔG for the two reactions together determines whether the reaction will proceed o ΔG of sequential reactions can be summed to give the overall free energy change for the process Coupling a very favorable reaction with an unfavorable one allows the overall process to proceed o The favorable reaction often used: ATP + H2O ADP + Pi ΔG = -30.5 kJ/mole PPi + H2O 2Pi ΔG = -30.5 kJ/mole o ATP hydrolysis is the main way energy is input into cellular procedures Essentially, energy is released into the surroundings, heating them up and increasing the disorder so that the total disorder of the universe increase Why is so much energy stored in ATP? o Charge separation Negative charges on β and Υ phosphates Energy required to push them close together, released when they separate o More resonance states in products Electrons are more spread out in Pi than the Υ phosphate on ATP Less electrostatic repulsion Phosphoryl Group Transfer Potential o How is ATP synthesized if it is so high in chemical energy? During oxidation of fuel molecules intermediary compounds are formed with phosphate groups that have even higher chemical energy than ATP Those extremely high energy phosphates can be transferred to ADP to form ATP o Increased resonance after phosphate group transfer is the reason these bonds are so high in energy Electrons more spread out, less compaction of negative charge Same reason as ATP Coupling of Oxidation to High Energy Phosphate Bonds o First carbon is oxidized One electron and one proton removed from fuel molecule, one electron and one proton removed from inorganic phosphate group (Pi) Two electrons and one proton transferred to NAD+ as an intermediate carrier Chemical energy released as C bonds to more oxygen o Then, coupled reaction transfers phosphate group to ADP Aldehyde has been converted to carboxylic acid (oxidation) Coenzymes: small organic or organometallic molecules that participate in the chemistry of enzymatic catalysis, form complexes with proteins (enzymes) o NAD+/NADH, which carries electrons taken from oxidized carbon is a coenzyme o Many enzymes require coenzymes for their mechanism Not always, some mechanisms can use only amino acid functional groups o Prosthetic groups: coenzymes that bind tightly and are not released bound to polypeptide by covalent bonds or strong noncovalent bonds o Some coenzymes, including NAD+/NADH, are not prosthetic groups These bind to enzyme then release and go to another enzyme So, NADH is an electron carrier Vitamins: small organic or organometallic molecules required in mammalian diets to prevent specific disease states o Many vitamins are converted into coenzymes Disease caused by loss of enzyme activity that requires a coenzyme derived from the vitamin o Mammals cannot synthesize the vitamins, so they must be obtained from the diet Plants and microorganisms synthesize the vitamins NADP+ Function o NADP+, NADPH function exactly the same as NAD+, NADH NADPH functions in anabolic reactions, electrons provided to carbon to make reduced compounds NAD+ functions in catabolic reactions, electrons taken away from carbon to oxidize it and release chemical energy Carrier Functions in General o ATP, NAD+, NADPH, FAD, CoASH all are carrier of “activated” groups They accept a “cargo” molecule from one compound and donate it to another All are in a high energy state after accepting the cargo molecule o Know which carrier correlates to what “cargo” ATP: phosphate groups NAD+, NADP+, FAD: electrons CoASH: acyl groups Biotin: CO2 groups Folic Acid: methyl groups B12: methyl groups o Note that all of these carriers are built onto nucleotides Likely established early in evolution Regulation of Metabolism o Enzyme concentration Determined by gene expression – responds to signal transduction pathways Synthesis and degradation of the protein o Allosteric regulation Feedback inhibition or feed-forward stimulation At the beginning of a pathway by the end product o Reversible enzyme covalent modification Phosphorylation by protein kinases Changes in disulfide bond structure o Substrate availability Ex Provision of glucose by opening of a gated transporter Biochemistry 301 – Survey of Biochemistry Professor Robert Thornburg LECTURE 16 – CHAPTER 16 – GLYCOLYSIS By: Emily Settle Overview of central metabolism o Glucose is central in metabolism High supply Glycogen stored in liver, starch in the diet – photosynthesis Stages of Glycolysis o Activation: two carbons starting in glucose are phosphorylated in transferase reactions ATP donates the phosphate group, ADP produced ATP hydrolysis provides free energy to the glucose molecule “charges” glucose for subsequent reactions Prepares for subsequent energy capture Rearrangement to fructose- 1,6- biphosphate Readily cleavable into two three-carbon compounds o Scission: splitting the six carbon compound into two three-carbon compounds o Resolution: oxidation steps Transfer of electrons to NAD+ Generation of “very high energy” intermediates Transfer of phosphate groups to ADP to generate the overall product, ATP o Glucose + 2ADP + 2Pi + 2NAD+ 2Pyruvate + 2ATP + 2NADH + 2H+ + 2H2O Activation Reaction 1 – Hexokinase o Induced fit of enzyme to substrate Excludes water Allows only the C6 hydroxyl of glucose access to the gamma phosphate of ATP Prevents hydrolysis of ATP, which would be wasteful Activation Reaction 2 – Phosphoglucose Isomerase o ΔG near 0 Aldehyde and ketone form have same oxidation states Reaction is driven in forward direction by rapid removal of product in the next step Activation Reaction 3 – Phosphofructokinase o Large –ΔG owing to coupled ATP conversion to ADP o Highly regulated step Scission Reaction 4 – Aldolase o The C atom adjacent to the carbonyl is involved in the catalytic mechanism Fructose is split into two 3 carbon compounds Glucose would split into one 2 carbon compound and one 4 carbon compound o In next step DHAP converted to Gly-3-P Thus, F-1, 6-BP is split into two identical molecules Scission Reaction 5 – Triose Phosphate Isomerase o Ketone converted to aldehyde Resolution Reaction 6 – Oxidation of Gly-3-P to 1,3-biphosphoglycerate (1,3- BPG) o Catalyzed by glyceraldehyde-3-P dehydrogenase o Product is very high in chemical energy, higher than ATP Aldehyde is oxidized, NAD+ reduced to NADH Energy freed by oxidation of carbon is stored temporarily in the acyl-phosphate o Energy released during oxidation of aldehyde is stored in the enzyme as a thioester Resolution Reaction 7 o 1,3-BPG 3-phosphoglycerate Catalyzed by phosphoglycerate kinase Coupled to phosphorylation of ADP (substrate-level phosphorylation) ΔG is negative even though ATP is produced o Steps 6 and 7 together Oxidation of aldehyde (G3P) to a carboxylic acid (3PG) Released energy used to synthesize ATP from ADP + Pi Resolution Reaction 8 o Starts process to create second very high energy mixed anhydride group How do we generate another high energy bond? 2 steps, move phosphate to middle, then move a double bond to the same location o 3-phospholycerate 2-Phosphoglycerate Catalyzed by phosphoglycerate mutase ΔG near 0, readily reversible reaction Resolution Reaction 9 o 2-PGA phosphoenolpyruvate (PEP) Catalyzed by enolase ΔG near 0 Dehydration forms PEP, a very high energy compound 2 steps, move phosphate to middle, then move a double bond to the same location Resolution Reaction 10 PEP pyruvate Catalyzed by pyruvate kinase Phosphate group transferred to ADP, forming ATP Very negative ΔG, essentially irreversible reaction o Even though ATP is produced from ADP (substrate- level phosphorylation) Product is enol form of pyruvate o Rapidly converts to the keto form o Product removal increases ΔG of the reaction 2 steps, move phosphate to middle, then move a double bond to the same location Fates of Pyruvate and NADH o NADH now must be oxidized back to NAD+ Nicotinamide in limited supply, from a vitamin (niacin) If NADH not re-oxidized, all nicotinamide would be in the reduced form No NAD+ available for glyceraldehyde-3-phosphate dehydrogenase reaction (or anything else) Metabolism could not continue Alcohol Fermentation o Yeast generates ethanol and CO2 in reactions that regenerate NAD+ o CO2 released by pyruvate decarboxylase Thiamine pyrophosphate required as a coenzyme Acetaldehyde is the other product o Reduction of acetaldehyde to ethanol Electrons for reduction come from NADH, NAD+ is produced o Conversion of glucose to ethanol and CO2 by yeast generates alcoholic drinks, and also causes bread to rise Lactic Acid Fermentation o Anaerobic conditions (bacteria, working muscle) Lactate fermentation Pyruvate reduced to lactate, NADH oxidized to NAD+ Catalyzed by lactate dehydrogenase Entry of other sugars into Glycolysis o Fructose and galactose are common in human diets Table sugar contains fructose, milk sugar contains galactose Regulation of Glycolysis (Intro) o Central control point is phosphofructokinase (PFK) F-6-P, G-6-P, can be diverted into other pathways F-1,6-BP is committed to glycolysis Committed steps are the major control points o PFK Inhibited by ATP as an allosteric regulator ATP is both a substrate and an allosteric regulator of PFK Two ATP binding sites, one catalytic and the other regulatory High AMP blocks the binding of the regulatory ATP, so prevents inhibition Further Regulation of PFK o Fructose-2,6-biphosphate is a regulatory molecule that signals glucose levels When glucose is high, insulin is released from pancreatic β cells Insulin signal transduction pathway results in production of F- 2,6-BP Phosphorylation state of the enzyme that makes F-2,6-BP changes when insulin So, F-2,6-BP is high when glucose is high o F-2,6-BP is an allosteric activator of PFK How does high glucose cause insulin release o 1 – glucose taken into cells o 2 – glucose degraded via glycolysis o 3 – ATP levels high o 4 – potassium pump increases o 5 – Ca2+ transported into cells o 6 - Calmodulins stimulate vesicle fusion with membrane o 7 – releasing insulin
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