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ERIC S. LANDER: It all works beautifully.
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You're getting sugar, you're producing ATP.
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What if you don't need so much ATP?
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What if you don't have so much sugar?
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Should we just have this pathway be running that way all the time or would
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you like it to be, if you're getting fancy, have dials on it, to be a
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little adjustable?
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STUDENT: Something tells me that.
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ERIC S. LANDER: Something tells you we're going to want
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some dials on that.
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So let's take a look at how we can regulate this nice pathway.
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A goes to B goes to C and maybe C could get used to make D, E, F, or
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maybe it could get used to make G, H, I. We're not going to fuss over any
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molecular structures here.
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Suppose we have too much F. The cell says, I've got too much F. I'm trying
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to balance things out.
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I've got too much F. Maybe F is ATP, maybe F is something else--
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I've got too much of it--
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yet this pathway's just churning out more of it.
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That's not good-- it's a waste.
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I don't want that much more F. What do you want to do?
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STUDENT: Turn it down.
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ERIC S. LANDER: I'd like to turn down the dial.
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What dial would I like to turn down?
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How about this one?
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If I turn down the dial here, I won't make so much F.
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STUDENT: [INAUDIBLE].
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ERIC S. LANDER: I'll make a lot of E, though.
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That's not so good.
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No.
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I could turn down this, but then I'll make a lot of D. Maybe what I should
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do is turned down this one.
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So you would like to have some way to have excess F and turn
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down the dial there.
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By the way, what's the dial that we're talking about?
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What is that arrow?
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That arrow refers to--?
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STUDENT: Rate.
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ERIC S. LANDER: Sorry?
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STUDENT: Rate.
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ERIC S. LANDER: The rate.
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And what controls that rate?
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STUDENT: Enzymes?
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ERIC S. LANDER: Enzymes are good at controlling rates.
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We can really slow things down if we could just persuade that enzyme to
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please stop working or work a little less well.
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So imagine if we had this enzyme.
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Here's our enzyme, and it's got a site here for C, and C, it's going to
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convert it into D. I'd like to have that enzyme please slow down if
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there's too much F. How's it going to know there's too much F and what would
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it do in response to it?
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STUDENT: Would F block the active site?
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ERIC S. LANDER: F might block the active site.
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That's a possibility.
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But probably F is a different shaped molecule.
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It doesn't fit in that active site so well.
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Yeah?
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STUDENT: Have a site for F that causes it to change shape so [INAUDIBLE]
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fit in.
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ERIC S. LANDER: So maybe there's some F binding place on the molecule.
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And when it binds F, it shifts its shape.
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Can proteins shift their shapes?
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STUDENT: Yes.
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ERIC S. LANDER: We saw proteins do a lot of shape shifting.
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So maybe there's an F site, and it changes its shape into another shape.
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The word for "other" in Greek is "allo." The word for "shape," three
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dimensional shape, is "stereo." This is called allosteric regulation.
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Other shape-- it just means other shape regulation.
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So F binds to that protein.
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And we were wondering, actually, weren't we, about this big protein
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with all these amino acids and all these things and what'd you
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need all that for?
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Well, some of that might be there because F can bind to it and then
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transmit the binding of F into its shape shifting and
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affect the active site.
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That's a pretty good trick.
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Suppose I have too much I.
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STUDENT: Same thing.
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ERIC S. LANDER: Same deal.
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I go back there.
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Suppose I have too much F and I. Where would I like to slow this thing down?
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Too much F and too much I.
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STUDENT: [INAUDIBLE].
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ERIC S. LANDER: I might want to slow it down over here.
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So maybe that enzyme--
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who knows?-- could have binding sites for F and I, a possibility.
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Now suppose it's not that I have too much product at the end of the
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reaction, but I have too much reactant at the beginning of the reaction.
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I've got too much glucose and I haven't made enough ATP.
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It's building up--
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I've got a lot of A. I want to get this reaction to go faster.
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I can't change the delta Gs, but I want this reaction to go faster.
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How am I going to get it to go faster?
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STUDENT: [INAUDIBLE]
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so you get to slow it down?
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ERIC S. LANDER: Well, these were things I slowed it down that way.
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But suppose I want to goose up.
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Yep?
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STUDENT: [INAUDIBLE]
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make that more favorable to it?
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ERIC S. LANDER: Ah, why can't I run allosteric regulation in the
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activation direction also?
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Maybe when As bind to a downstream enzyme, it activates the enzyme and
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makes it better.
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So I can run that both ways.
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STUDENT: Is that what you said happened in the hemoglobin, sort of?
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ERIC S. LANDER: Well, in the hemoglobin, that's a
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little bit like it.
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It's not quite the same thing, but when one oxygen bound in hemoglobin,
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it made it more favorable for another one for the-- so in fact, hemoglobin
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changed its shape to make more binding possible.
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Hemoglobin is not an enzyme, but it's exactly the same principle.
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It's allosterically changing to improve binding, and what you're
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saying is we could allosterically change to improve our
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enzyme speed as well.
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So we can have either--
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we could call the first thing we talked about feedback inhibition, or
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we could have feedforward activation.
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And that happens--
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it happens all over the place.
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Probably when this reaction first evolved in evolution there, long, long
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time ago, it didn't have all those nice tweaks.
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But over time, as organisms competed with each other, those who evolved
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cute tricks like being able to do feedback inhibition or feedforward
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activation outcompeted their friends and all of these cool little tricks
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were layered on top and on top and on top.
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So we actually see this happening in glycolosis.
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Glucose to glucose-6-phosphate.
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First step, glucose to glucose-6-phosphate.
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That's an expensive step, isn't it?
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I'm spending an ATP.
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Well, suppose I have a lot of glucose-6-phosphate around.
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Would I want to do that?
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It turns out glucose-6-phosphate itself can inhibit the enzyme that
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makes glucose-6-phosphate.
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Pretty cool.
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That enzyme's called hexokinase, because kinase means puts a
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phosphate group on.
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And so the product actually inhibits the enzyme and says, if I've got too
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much product, please don't bother making any more.
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Now there are some other things here.
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Some of these other things here can be inhibited by too much ATP.
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Don't got enough ATP?
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I can inhibit them, because there's an ATP binding site.
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If I've got too little ATP, then there's too much ADP, or actually,
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often the molecule that has just one phosphate, adenosine monophosphate,
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and those guys can come back and they can activate.
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And in fact, this is an incredibly important and an expensive pathway.
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I'm spending ATPs and it's highly regulated along the way.
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So that's what happens there.
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There's actually a lot of a lot of fancy tricks that I won't get into,
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and not all the regulation for most pathways is even fully understood
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because they're still probably lots of aspects we don't fully know.
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All right.
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Take a moment and test yourself with a pretty hard question about the
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regulation of pathways.
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