YouTube Transcript:
Gluconeogenesis

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in today's video we are going to be

tackling everything that you need to

know about gluconeogenesis this is

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in today's video we're going to be

talking about gluconeogenesis

let's start with an overview and then

we'll do a high yield rapid review where

we run through the pathway

and i'll point out the few things that

you guys need to know so that you can go

into test day feeling confident that

you're going to get 100

of your questions on gluconeogenesis correct

correct

so just as an overview gluconeogenesis

is the process

by which the body maintains eu glycemia

which means keeping blood sugar levels

within the normal physiologic range

and that euglycemia is maintained by

producing glucose from

non-carbohydrate sources gluconeogenesis

occurs mainly in the liver and the kidney

kidney

and it occurs both in the cytosol and

the mitochondria

this pathway typically occurs during

fasting when the body

needs to continue to make a source of

glucose but doesn't have any input glucose

glucose

now of note skeletal muscle cannot

undergo gluconeogenesis

and that's due to the absence of glucose

6-phosphatase which is a key enzyme

involved in gluconeogenesis the way to

conceptualize gluconeogenesis

is to think of it as glycolysis in reverse

reverse

so to refresh your memory in glycolysis

you start with glucose

and you end with pyruvate and in between

there's all these

messy nasty looking steps that most of

which you actually don't need to know

for us emily or comlex and then once you

have pyruvate that pyruvate can be shuttled

shuttled

either to lactate through the cory cycle or

to alanine through the cahill cycle

there are also other destinations for

pyruvate but those two cycles

allow you to convert lactate or alanine

into pyruvate and once you have pyruvate

you're really in a flexible position

because pyruvate can enter any one of

those pyruvate pathways

or in the case of gluconeogenesis you

can go

back up from pyruvate back to glucose

and in this

process you'd be able to synthesize glucose

glucose

potentially from a non-carbohydrate

source such as lactate or alanine

so in gluconeogenesis i'm going to make

a blanket statement here

it is glycolysis in reverse so every

single step

going back up from pyruvate back up to glucose

glucose

is going to be the same exact step

in reverse that you saw in glycolysis

the only exception to what i just said

are three steps so going from pyruvate

back up to glucose everything is the

same as glycolysis

just in reverse with the exception of

three steps

and because only three steps are

different you only need to know these

three steps

okay so this is really all you need to

know for usmle or comlex

so let's go back up one at a time going

through these steps

we'll talk about the different enzymes

we'll talk about what's different

between gluconeogenesis

and glycolysis so the first step is

actually a two-parter

it converts pyruvate into oxaloacetate

and the enzyme that does this conversion

is pyruvate carboxylase

the second mini step within this first step

step

is to convert oxaloacetate into phosphoenolpyruvate

phosphoenolpyruvate

through the enzyme phosphoenolpyruvate carboxy

carboxy

kinase so big picture here the first

step is to get pyruvate

to phosphoenolpyruvate and depending on

what review source you're using or what

question bank you're using

you might see that abbreviated as pep pep

pep

phosphoenol pyruvate so pyruvate to

oxaloacetate and then oxaloacetate

to phosphoenol pyruvate now the next

step occurs later on so it's not right above

above

pep that's why i made the little arrow

have the dashed sign so somewhere

back up as you continue to progress back up

you have another major difference

between gluconeogenesis

and glycolysis and in this one you're

starting with fructose 1

6 bisphosphate and you're converting it

to fructose

6 phosphate so you're kind of just

chopping off that one phosphate

the enzyme that does this is fructose 1 6

bisphosphatase now by and large i'm a

big believer in trying to make things

stupid and simple

if you look at what you're starting with

which is fructose 1

6 bisphosphate and what you're ending with

with

fructose 6 phosphate you're really just

dropping that one phosphate like i said

so the enzyme fructose 1 6 bisphosphatase

bisphosphatase

should make perfect sense because you're

tasing off that one phosphate

so now you've got fructose 6-phosphate and

and

somewhere going back up the last major

difference between gluconeogenesis

and glycolysis is you start with glucose 6-phosphate

6-phosphate

and you convert it back to your desired

target of glucose

using the enzyme glucose 6-phosphatase

so guys and girls these three steps

which you see within these

gray boxes are the only difference

between gluconeogenesis and glycolysis

and if you want to think big picture

here the reason why there's only

these three steps that are different is because

because

the body needs gluconeogenesis when it's

in a period of fasting

and in a period of fasting there's not

readily available

atp to be used to synthesize glucose

through gluconeogenesis

after all the whole reason that the body

even wants to synthesize glucose

is because it needs to maintain

euglycemia so that we can make

glucose out of a non-carbohydrate source

to then in turn use that glucose to make

more atp

and to continue to power the cells in

our body

even in the absence of a carbohydrate source

source

so because of that the body has very

specially evolved

these three or four enzymes in gluconeogenesis

gluconeogenesis

to provide a system of checks and

balances as you might imagine if

gluconeogenesis was just going

all the time not requiring specialized regulation

regulation

at these checks then the body would be

wasting a lot of energy

and the idea is that the body's in a

fasting state already it needs more

energy it can't just be

silly willy doing gluconeogenesis so these

these

enzymes are extremely important in

protecting the cells and protecting

the very limited scarce amount of

glucose that's in the body

and in turn of atp that's in the body

so big picture lactator alanine can be

converted into pyruvate

as well as some other precursors and

then pyruvate can go back

all the way up to glucose to provide a

glucose source

from a non-carbohydrate origin to power

the cell and make more atp

now for usmle or comlex what you

absolutely need to memorize and it's the

most important thing in this video today

is that fructose 1 6 bisphosphatase is

the rate limiting step

of gluconeogenesis on these exams

the writers love to ask you what the

rate limiting step is so you absolutely

need to know

that f16bp is the rate limiting enzyme

of gluconeogenesis the other thing

that's important to know is the

regulation of these enzymes so on the

right side of this slide i'm going to

fill in the regulation now

at fructose 1 6 bisphosphatase that

enzyme is activated by citrate

but it's inhibited by amp and fructose

2-6 bisphosphate fructose 2-6 bisphosphate

bisphosphate

and amp should make a bit of sense if

you think about what's really happening

in the fed state after the after

somebody were to eat

you would undergo glycolysis because

you'd have readily available glucose

that can be broken down and recall from glycolysis

glycolysis

go watch my glycolysis video if you need

to have this explained more

but in glycolysis you see increased

levels of fructose-2-6-bisphosphate

so it should make sense to you that if

there's fructose-2-6-bisphosphate lying around

around

it's going to inhibit an enzyme involved

in gluconeogenesis

because it promotes glycolysis and you

don't want both of those pathways acting

at the same time

that would just make no sense at all down

down

for phosphoenolpyruvate carboxykinase

that step requires gtp

and at pyruvate carboxylase that step

requires biotin additionally acetyl coa

activates pyruvate carboxylase and if

you think about it

citrate and acetyl coa are both involved

in inhibiting

glycolysis so it should make a little

bit of sense that at various points in gluconeogenesis

gluconeogenesis

they actually support gluconeogenesis

lastly the big picture regulator of gluconeogenesis

gluconeogenesis

is glucagon and everything that is

glucagon genic i'm probably making that

word up but what i mean by that

is that glycolysis happens in response to

insulin insulin breaks down glucose and flows

flows

downward from glucose to pyruvate and

the opposite is true

of glucagon so when you don't have insulin

insulin

you have glucagon so glucagon inhibits glycolysis

glycolysis

and promotes gluconeogenesis on usmle

and comlex

much of biochemistry can be simplified

by remembering that if you have insulin

you don't have glucagon and if you don't

have insulin

you do have glucagon and therefore if

there's an enzyme that you know

is regulated by either one of those hormones

hormones

insulin or glucagon you can just think

of them as opposites

now you understand the rate limiting

enzyme and now you understand regulation

the last part of this which i'm sure

you've been wondering this entire time

is how do i remember this how do i remember

remember

the three different steps of gluconeogenesis

gluconeogenesis

that make it unique from glycolysis and

if you take a look at what we have here

working from the bottom

up or working from pyruvate back up to glucose

glucose

we have pop ffgg

pop pyruvate oxaloacetate

phosphoenolpyruvate ff for the fructoses

in fructose 1 6 bisphosphate and

fructose 6-phosphate

and the 2gs in glucose 6-phosphate and glucose

glucose

so my way of remembering this is that in

the fasting state

when gluconeogenesis would need to occur

you're going to

pop fresh gouda pop fresh gouda

right you're going to pop that fresh

cheese right in your mouth because you're

you're

fasting and you're hungry pop pop

pyruvate oxaloacetate phosphoenol pyruvate

pyruvate

the two fs for fresh fructose 1 6

bisphosphate fructose 6-phosphate

and the 2gs for gouda the g is coming

from glucose 6-phosphate

and glucose so like i said at the start

of this video

not a whole lot to know for

gluconeogenesis but if you're going to

take away a couple big picture ideas

it's glycolysis in reverse with the

exception of pop fresh gouda

the rate limiting enzyme is f16bp

and know the regulation which you see on

the right side

of this slide that's really all you need

to know and if you're comfortable with

that information you'll get all of your

questions correct

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YouTube Transcript:
Gluconeogenesis