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JOANNE STUBBE: What I want to do is sort of introduce you

to the second half of the course, where we're going,

and what topics we're going to be covering.

And then I'll start in module 5.

So as with the first half of the course, we have four modules.

The first half the courses was pretty well organized--

that is, you went from here to here to here.

It all sort of made sense.

This half of the course doesn't do that.

We're talking about-- there are hundreds

of topics in biochemistry, and any one of them

is exciting and important.

And these are the ones we're talking about this semester.

And again, the focus will be sort

of trying to get you to think about,

what is the evidence that supports

the model I'm going to present.

So in module 5, we're going to be talking about the terpenome.

And I'm going to be talking about, most of you

have seen in the last module, with polyketide synthases,

you have aldol reactions and claison reactions

to form carbon carbon bonds.

In this module, you're going to be introduced to another way

to form carbon carbon bonds.

And that's through C5 units.

And C5 units are the basis for forming cholesterol, which is

really the focus of module 5.

And what we're going to be talking about

is initially cholesterol biosynthesis,

that will be this lecture and probably

most of the next lecture.

And then you all know from eating McDonald's hamburgers,

you get a lot of cholesterol in your diet.

And the question is, how do you control cholesterol levels?

And so this semester, the second part of the semester

is really focus on the question of homeostasis.

Cholesterol is essential.

If you have too much you've got problems.

Doesn't matter what pathway you're talking about,

if you have too much or you have too little, you have problems.

So how do you control everything?

And we're going to be talking about cholesterol sensing

and regulation.

And we're going to come back to a topic you covered

in the first half of the course with ClpX and ClpP protein

mediated degradation, because it plays

a central role in controlling cholesterol homeostasis.

So that will be the first module, module 5.

Module 6 is also going to be a module on homeostasis.

It's my feeling that in introductory courses,

people don't get introduced enough to metals.

And 50% of all the proteins inside of us

bind metals and do something with them.

And so in this module, I'm going to talk

about metal homeostasis.

And I'm really going to focus on iron.

And you'll see why I'm going to focus

on iron when we get there.

But we're going to talk about iron sensing and regulation,

initially in humans, and then we're

going to focus on the war between pathogenic organisms

for iron and humans for iron, since iron

is essential for almost all organisms to survive.

The third module is sort of--

module 7-- sort of follows from module 6.

And it's a topic that I've been following for 30 years,

and it irritates the hell out of me.

So everybody talks about reactive oxygen species,

and how bad they are.

You can't-- you can listen to NPR,

you can read it in The New York Times.

What are reactive oxygen species?

As a chemist, what are they?

So we'll define what reactive oxygen species are.

Many of you know that they're bad.

That's why you eat vitamin C and vitamin E.

And they're involved, in fact, in defense

against some microorganisms.

But also they're good.

They're now known to be involved in signaling.

So again, it's a question of homeostasis.

And so you need to understand the chemistry

of what these species do, and where they can go astray,

or where you can harness the reactivity

to do something important.

And the last section-- hopefully we'll get there this year,

I'm trying my best--

this is the area I know most about,

we're going to talk about nucleotide metabolism.

In 5.07, they don't talk about nucleotide metabolism at all.

And I would say in the next decade,

you're going to see a lot about nucleotide metabolism.

Where have you seen ATP and GTP in the first part

of this course?

Everywhere.

How do we control all of that?

Pretty important.

What are the questions we're going to be asking?

Where does it come from?

And how do we control the levels,

which is central to all of metabolism?

Hopefully we'll get there and discuss that.

So the required reading has now been posted on Stellar.

And there are-- there is really sort of three

things you need to read.

One is about a short review on the terpenome, which

is what I'm going to start talking about.

The second is lipid metabolism that's

been taken from Voet & Voet, you can

go back in any basic textbook and read the section,

because it's central to thinking about what's

going on with cholesterol.

And then you'll see that these are

two of my favorite guys, Brown and Goldstein.

They won the Nobel Prize for their work,

but in reality they should have won at least two Nobel prizes

for their work.

I mean, you can never not listen to them talk

and not get excited.

I mean, they always have something

important and exciting to say.

So they-- last year we used this review.

There's a new review.

They're different, they're both pretty short.

Pick which one you want, they cover the material.

And then this one doesn't cover the most recent material

as well.

So here's another short review that covers that material.

So these guys here will give you an overview of what

I'm going to be talking about.

And they've all been posted on the website already.

So cholesterol homeostasis--

I never end a lecture on time.

You'll find out that I'm trying my best, anyhow.

We have about five lectures we're going to be covering.

And this is where we're going.

And the first one, today's lecture, we're

going to be talking about a new way

to form carbon carbon bonds through C5 units.

And we'll be talking about the terpenome, where

there are a huge number of natural products,

distinct from polyketide synthases

and non-ribosomal polypeptide synthases

that you just finished talking about.

We want to get to-- we'll see in the biosynthetic pathway

to get to these C5 building blocks,

we need to get to a metabolite called mevalonic acid, that's

front and central in cholesterol biosynthesis.

So we need to get that far.

And then we need to get from mevalonic acid

into cholesterol.

And so we'll be talking about this the first couple

of lectures.

In addition to making cholesterol,

you get a lot of cholesterol from your diet.

And so the question is, how does it

get from your diet, transferred through the plasma,

and taken up into cells?

And this section, we'll describe the discovery

of receptor mediated endocytosis,

by Brown and Goldstein, that's now known

to be prevalent everywhere.

So the module-- module 6, you take up

iron by receptor mediated endocytosis.

In module 7, growth factors are involved in receptor mediated

endocytosis.

So it represents a general paradigm

that happens all the time over and over again in biology.

And then we're going to ask the question,

how do you sense the cholesterol?

And we're going to be doing two recitations on this.

And then we'll have a few lectures on the machinery

that sense cholesterol sterile responsive binding proteins,

in a molecule called SCAP, and another molecule--

both of these are proteins-- called INSIGs.

Everything is located in a membrane-- that's something

you haven't been exposed to.

How do you control everything when you

have stuff stuck in a membrane.

And then we'll come back at the end

to look at the rate limiting step

in formation of mevalonic acid, HMGCoA reductase,

and how that plays a key role, since it's

involved in making cholesterol.

How do we control and regulate that protein, also

in the ER membrane.

And we'll see it requires ubiquitin mediated protein

degradation.

And so that's why I'm going to come back,

and we're going to spend a little bit of time

talking about this process in eukaryotic systems.

And actually, in all the other modules,

you're going to see ubiquitin mediated protein degradation.

And finally, this week in recitation, there's a new--

not new, it was discovered in 2003--

a new target for drug therapy in controlling cholesterol levels.

And there was a paper published this year

to show that this is, in fact, a good target.

And this paper used CRISPR-Cas9 technology.

So I'm going to--

even though I'm not an expert in that, my lab hasn't used it--

I'm going to introduce you to this technology,

and then focus on why we think this is a good new target,

and what the targeting is.

So that's where we're going.

So the terpenome-- let's see if I can

remember what I'm going to say.

The first thing I want to say is-- let me just get all this--

OK, the first thing I want to tell you something about

is the nomenclature--

and all terpenes are either called

isoprenoids or terpenoids, and they're all made from C5--

a C5 hydrocarbon skeleton.

And this C5 hydrocarbon skeleton is an isoprene.

So this is the key building block

that you're going to see over and over again

over the course of the first couple of lectures.

So an isoprenoid is, in general, linear.

And it's made of n of these C5 units.

So n can be 2 to thousands.

And I'll give you examples of these.

And again-- and then the terpenoids--

so let's just use terpenoids over here--

in general are also made of C5--

C5 units.

But often, they're oxidized, cyclized,

and sometimes rearranged.

So my goal today really sort of is introduce you

to this huge class of natural products.

And give you some examples of this,

and then start focusing on how we get the building blocks.

Do you think iso--

this isoprene can be a building block?

It's chemically not very reactive.

So no, we have to convert--

we have to convert this into the chemically reactive building

block.

So while isoprene gives you the C5 unit,

our focus today is going to be on creating the building

blocks.

And again, the building blocks are going to be--