4 - Lecture notes 23 PDF

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Lecture 23 - 4.18.19...

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4/18/19 Metabolic pathway regulation o Metabolic pathways must be regulated  They must be regulated so that the reaction occurs when needed, and they are not allowed to happen at any point in time so that cells [that have a finite amount of energy] can conserve the energy and direct it to where it is useful  Release energy when required  Store “extra” energy  Synthesize molecules when needed o Specific reactions (enzymes) serve as key regulatory steps  Large -∆G’s reactions  Irreversible reactions  These reactions are regulated o These reactions are highly exergonic and doesn’t want these reactions to occur unless all the energy that is released will be captured and used for other purposes  Over evolutionary time, large -∆G reactions were selected to be regulated  Conditions cannot be altered to make them reverse o Once products are made, the cell is committed to using the products  Limits the possible options o Enzymes for irreversible reactions (large -∆G) needs different enzymes to carry out the reverse reaction  ∆G’s near zero  Conditions can be altered to make reactions reversible o Reversible reactions are advantageous in the cell since it allows the cell to redirect intermediates along different pathways  Reactions near equilibrium are reversible o Conditions in the cell allow for both the forward and reverse reactions to happen  Forward and reverse reactions have similar reactants and products  Many pathways are interconnected and sometimes there are shared reactions between pathways  Regulatory enzymes are often at the beginning or end of a pathway  “Committed step” is often regulated  A reaction commits the products to that particular pathway  Frequent target for regulation o If a chemical reaction in one direction is irreversible, then the opposing pathway [if it occurs], uses a different chemical reaction and different regulatory enzymes  There are different regulatory enzymes for opposing pathways

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Allows independent regulation (“fine tuning”) based on cellular conditions o Since they are different enzymes, the pathways can be altered differently o A cell can target one enzyme to regulate its activity and also target or not target the enzyme for the reverse reaction

o Muscle cells  Use a variety of fuel sources  Fatty acids at rest, glucose during exertion  Vary widely in their energy demands  Sometimes need a lot or a little  Use glycogen stores only for itself  Does not share  Glycogen break down exceed synthesis by 300-fold  Do not respond to glucagon  Do not perform gluconeogenesis, fatty acid synthesis or ketogenesis  Muscle cells perform these pathways infrequently and very rarely o Liver cells  Use a variety of fuel source  Fatty acids and glucose  Changes depending on physiological conditions  Important for fatty acid homeostasis (triglycerols formation and fatty acids synthesis)  Storage site for glucose with equal rates of synthesis and break down  Directly regulate blood glucose levels in response to hormones  Are the primary sites for synthesis of ketone bodies [although they do not use the ketone bodies] o Enzyme activity  Liver and muscle cells need to be able to respond and increase or decrease any individual pathway by receiving information from inside or outside the cell  Activity of regulatory enzymes are controlled by internal and external signals  Internal signals  Reflect conditions in a particular cell  Substrate availability  Cofactor availability  Activators/inhibitors  Feedback inhibition 

External signals

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Provide information about conditions in the organism Activators/inhibitors Hormones

o Hormones  Primary method of regulation used to control metabolic reactions  Mediate phosphorylation/dephosphorylation to influence activity of enzymes  Chemical signal produced [by endocrine cells that are not local] in response to a specific condition, and “broadcast” throughout an organism via the blood stream  Not every cell will respond to a hormone  Only interacts with target cells that have receptors for a specific hormone to alter its behavior  Hormone receptor proteins are specific  Receptors interact with one [or a few] hormones o Only the cells with the receptors will respond  Same hormone can cause different responses in different cells o Different receptor = different response o Same receptor = different response  There must be something different from the moment the hormone binds to the receptor and a downstream effect to cause different responses  Hormones binding to cell membrane receptor proteins function via same basic mechanism  Interaction of hormone causes receptor protein to change shape (conformational change) and send a signal to another molecule (Gprotein) inside the cell  Triggers production of multiple second messengers o Molecules that activate/inhibit enzymes o Activation of one receptor could lead to production of multiple 2nd messengers  Alter activity of metabolic pathway enzymes to cause a cellular response o 2nd messengers can directly or indirectly lead to activation of ≥1 enzyme (kinases or dephosphatases)  Leads to amplification of signal Explains why a small amount of hormone results in a big effect on a cell...