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METABOLIC BIOCHEMISTRY. Lecture 20 March 10, 2005 Summary and Review. Metabolism - The overall process by which living systems acquire and utilize free energy to carry out biological work - The process by which a variety of small molecules are assembled from a few
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METABOLIC BIOCHEMISTRY Lecture 20 March 10, 2005 Summary and Review
Metabolism • - The overall process by which living systems acquire and utilize free energy to • carry out biological work • - The process by which a variety of small molecules are assembled from a few • precursors; the small molecules then serve as building blocks for • macromolecular structures • Metabolism can be organized into pathways: these pathways may overlap, • and branch, and even consist of circular paths • A pathway consists of consecutive enzymatic reactions: the reactants, • intermediates and products are called metabolites • - The flux through each pathway is regulated by a sophisticated set of • metabolic regulatory mechanisms: feedback inhibition, allosteric interactions, • covalent modification of proteins/enzymes, etc. • - Over a 40 year time span a human being consumes tons of nutrients and • imbibes 20,000 liters of water, yet remains more or less at steady state
-Metabolic pathways are irreversible at certain key steps where a large negative • free energy change occurs • -There are catabolic pathways (e.g.glycolysis) and anabolic pathways (e.g. gluconeogenesis);these are necessarily different at key steps, but may share some steps • -In eukaryotic cells the various metabolic pathways are compartmentalized: • cytosol, mitochondria, peroxisomes, chloroplasts, etc. • -The compartments are defined by membranes; special transport mechanisms must • exist to regulate the flow of reactants and products in and out of a compartment • In some cases the flow is determined by a concentration gradient (diffusion), but stillrestricted by a specific transporter; • in other cases integral membrane proteins can act as pumps to pump metabolites • and ions against a concentration gradient; this requires an input of energy
Why study metabolism and its regulation? 1. This is what scientists do: it is an intellectual challenge The final result is satisfying and even beautiful (although beauty is in the eye of the beholder) 2. It turns out to have enormous practical value in the maintenance of our good health a) a common sense approach to nutrition b) an intelligent response to false advertising in understanding “metabolic diseases” (inborn errors of metabolism) a) diagnosis b) possible treatments c) establishing a genetic basis d) genetic counselling and prenatal diagnosis 3. you can make a lot of money (drugs, inhibitors, etc.)
POWER = WORK / TIME (Physics) TIME = MONEY (Business) KNOWLEDGE = POWER (Academia) WORK KNOWLEDGE = ______________ (1) MONEY Solving for money: WORK MONEY = _________________ KNOWLEDGE
If the true essence of life is the accumulation of experience through generations, then one may perhaps suspect that the key problem in biology from the physicists point of view is how living matter manages to record and perpetuate the experience Max Delbruck Mitchell’s CHEMIOSMOTIC HYPOTHESIS is one of the giant achievements of 20th century science It can almost literally explain how solar energy can be converted into force and kinetic energy (e.g. muscular motion) or electrical signalling between the brain and our peripheral nervous system
Fatty acids Glycogen Glyoxylate Cycle Glucose Acetyl-CoA PEP Krebs Cycle Calvin Cycle mevalonate CO2 Cholesterol etc. CO2 Urea Cycle Electron Transport OXPHOS Light Reactions
KEGG Kyoto Encyclopedia of Genes and Genomes
OMIM Online Mendelian Inheritance in Man
glycolysis gluconeogenesis glucokinase phosphatase phosphofructokinase PFK-1 phosphatase PEP carboxykinase pyruvate kinase pyruvate carboxylase 4 ATP, 2 GTP, 2 NADH needed 2 ATPs produced
MUSCLE LIVER
b-oxidation of fatty acids: 1. Activation in cytosol to acyl-CoA 2. Transacylation to form acyl-carnitine 3. Import into mitochondria 4. Transacylation to acyl-CoA 5. Four steps in b-oxidation
1. in plants 2. long chain FA in animal cells
acetyl-CoA + acetoacetate lyase decarboxylase dehydrogenase acetone b-hydroxy-butyrate
[4Fe-4S] [2Fe-2S]
x atractyloside
x x x x cyanide malonate rotenone antimycin
5 C3 -P 3 C5 - P aldolase C3 + C3 C6* C6* C6 C6 + C3 C4 + C5 C4 + C3 C7* C7* C7 C7 + C3 C5 + C5’ phosphatase transketolase aldolase phosphatase transketolase