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Glycolysis

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welcome back to the high-yield

biochemistry series this is brought to

you by dirty medicine in today's video

we're going to continue our discussion

about the biochemical pathways and talk

about glycolysis glycolysis is typically

the first biochemical pathway that you

learned when you're learning about

biochemistry and it's because of that

that it's extremely high yield shows up

on exams all of the time now when you're

learning about glycolysis as you'll see

me mentioned throughout this video it's

really important to remember the bigger

picture and when I say that I'm

referring to things like what is the

function of the role of glycolysis what

are we taking as a reactant and turning

into a product and what are the

regulatory mechanisms in terms of

feedback so what makes this go forward

what inhibits this and what is the

rate-limiting enzyme just like all of

the biochemistry videos that I've

created you need to know the

rate-limiting enzyme and the regulatory

mechanisms so we're talking about things

like inhibitors etc so let's start with

a quick overview of glycolysis

glycolysis is an irreversible

biochemical reaction that occurs in the

cytoplasm the net equation for

glycolysis is that you start with

glucose and the goal is to take that

glucose and turn it into pyruvate where

it can downstream take multiple pathways

through that pyruvate pathway and

preferentially usually this goes into

the citric acid cycle but here's the net

equation you've - you start with glucose

and you add two phosphates two ATP's and

two and a DS and what you get out of

that is two pyruvates plus two ATP's

plus 2 NADH plus two hydrogen's plus two

waters but if you wanted to just think

very simply about what glycolysis is

doing it's taking glucose and breaking

that glucose down into storable products

that the body can use in other

biochemical pathways so now that we've

understood the overview of glycolysis

let's just get

to the the meat and potatoes here we're

gonna talk about the pathway you need to

understand the pathway and I'm gonna pay

very special attention to the regulatory

mechanisms of this pathway and the

rate-limiting enzyme so you start with

glucose right any person takes a bite of

a cheeseburger eats a french fry drinks

a milkshake and they've got a bunch of

carbohydrate in their body and that

carbohydrate is composed usually of

glucose and if it's not of glucose then

the other types of sugars will get

turned into glucose

so that glycolysis can utilize it the

first step is glucose will get turned

into glucose 6-phosphate glucose

6-phosphate will get turned into

fructose 6-phosphate fructose

6-phosphate will get turned into

fructose 1 6 bisphosphate and now you've

got like multiple steps that are gonna

happen there's gonna be four or five

more reactions in this pathway and

you'll end up with phosphoenolpyruvate

which will get turned into pyruvate and

going from glucose down to pyruvate is

the entire glycolysis pathway so when

you get to pyruvate you're basically

finished with glycolysis now let's talk

about the important enzymes that you

need to know so the first step that

converts glucose to glucose 6-phosphate

there's actually two different enzymes

that can be used depending on the

circumstances of the glucose

concentration and where in the body

we're talking about so those two enzymes

are glucokinase and hexokinase so to be

perfectly clear either glucokinase or

hexokinase can convert glucose to

glucose 6-phosphate and what you'll need

to know for test a that's really high

yield is to understand under which

circumstances both of these enzymes

might be used

so for gluco kinase this enzyme has a

low affinity and a high km just remember

the reciprocal relationship between

affinity and km the higher the km the

lower the enzyme has an affinity for its

substrate so glucokinase has a low

affinity for glucose it typically

doesn't want to go and grab glucose and

the reason for this is because

glucokinase acts as a glucose

sensor its present in the liver and the

pancreatic beta-cells and it's only used

when glucose is at high concentrations

so basically what you should think of

glucokinase s is an emergency enzyme

that is acting as a glucose sensor and

it's really not grabbing glucose because

instead of grabbing glucose and breaking

it down through glycolysis what it's

doing is it's sensing glucose and it's

going okay let's test how much glucose

is over here and that's okay we're not

gonna jump in yet

HECO kinase you go first so hexokinase

on the other hand that is a high

affinity enzyme which means it has a low

km and because it has high affinity for

its substrate hexo kinase is the one

that's constantly going to be latching

on to glucose and converting it to

glucose 6-phosphate and sending it down

the glycolysis pathway and the reason

for that is because hexo kinase is the

enzyme that's used to operate the basal

glucose metabolism so constantly

throughout your body in all of your

tissues you have this enzyme hexokinase

that's just keeping a basal level of

glucose metabolism present it's trying

to make sure that your glucose level is

adequate throughout the body in all of

the tissues but if hexokinase becomes

overwhelmed because suddenly there's a

massive influx of glucose that is when

hexa kinase turns to glucokinase and

says gluco i know you usually have a low

affinity but i really need some help now

because the glucose concentration is

high so if you think about it that's the

reason that glucokinase is only found in

the liver and the pancreatic beta-cells

because it does a very specific

regulatory job where it's only acting

when the blood glucose levels are super

super high when that concentration

reaches some critical point that's when

glucokinase in the liver and the

pancreatic beta-cells

jumps in to save hexokinase so the

takeaway from this slide is that both

glucokinase and hexokinase are enzymes

that catalyze that conversion from

glucose to glucose 6-phosphate the only

difference is that hexokinase is kind of

there all of the time making a basal

level of glucose and glucokinase jumps

in in emergencies but understand the

differences between those two enzymes

that I've put in the gray boxes they are

extremely high yield and probably will

show up on your test so here's where we

are we've we've talked about the enzymes

in the first step the enzyme that

converts fructose 6-phosphate to

fructose 1 6 bisphosphate is the

rate-limiting enzyme of glycolysis and

that's phosphofructokinase 1 sometimes

you'll hear this referred to as PF K 1

so PF k 1 or phosphofructokinase 1 is

the rate-limiting enzyme and it converts

fructose 6-phosphate to fructose 1 6

bisphosphate now I told you at the start

of this video that the very important

thing to keep in mind for USMLE and

comlex is the regulatory mechanisms and

what I mean when I say regulatory

mechanisms are what inhibits this

pathway and what promotes this pathway

and we're going to talk about that for

the first time right here and because

phosphofructokinase 1 is the

rate-limiting enzyme it's really high

yield to understand what inhibits

phosphofructokinase 1 and what promotes

phosphofructokinase 1 and that's what

you see here so ATP and citrate will

inhibit the rate-limiting enzyme pfk one

but a MP will promote the rate-limiting

enzyme of pfk 1 and this should be

somewhat intuitive to you so so think

about what glycolysis is doing the role

of glycolysis is to take glucose convert

it to pyruvate and ATP and then let that

pyruvate enter one of many different

pathways but usually the citric acid

cycle where you'll then create citrate

so if you think about that the question

becomes what would this pathway want to

do if it already had ATP and therefore

didn't need to make it or if it already

had citrate and therefore didn't need to

make pyruvate which would then go to

citrate and that's why ATP and citrate

inhibit pfk one because if you have ATP

and you already have citrate then you

don't need to do glycolysis so the

presence of those products will inhibit

the rate-limiting enzyme and therefore

glycolysis won't occur now likewise

think about AM P if you have AM

which is mono phosphate only one you

don't have ATP and therefore if you

don't have ATP you want to do glycolysis

so in the presence of a MP which is to

say in a situation where you don't have

ATP a MP will promote PF k1 and will

therefore promote glycolysis so anytime

you're not really sure about how the

regulatory mechanisms are working think

about this intuitively ask yourself on

test say well would glycolysis happen if

there was a MP would glycolysis happen

if there was citrate it should make

sense to you if you understand what the

big picture role of these pathways are

so that's what promotes and inhibits pfk

one now I need to pause for a second and

tell you about this little nuance of

glycolysis so fructose 6-phosphate can

can go to fructose 1 6 bisphosphate as

you see on this slide but additionally

there's sort of a side step that occurs

a pivot if you will fructose 6-phosphate

can also become fructose 2 6

bisphosphate and if fructose 6-phosphate

will become fructose 2 6 bisphosphate

the enzyme that catalyzes this

conversion is phosphofructokinase 2 pfk

2 so very similarly named of course to

the rate-limiting enzyme that we just

talked about but instead of one it's two

so when this happens you create fructose

2 6 bisphosphate and interestingly that

fructose 2 6 bisphosphate will promote

pfk 1 so the goal when the body does

this is to make glycolysis happen faster

now the question then becomes what is

promoting or inhibiting

phosphofructokinase 2 or pfk 2 and

that's really simple so it's gonna be

inhibited by glucagon and it's gonna be

promoted by insulin so think about it if

fructose 2 6 bisphosphate makes

glycolysis happen faster and in

glycolysis you're breaking down glucose

it makes sense that insulin will promote

pfk 2 because in the presence of glucose the

the

body's gonna secrete insulin and the

body's telling anything that any cell

that has a glycolysis pathway occurring

it's like yo take that glucose break it

down please get this out of the system

and that's insulins roll the opposite of

that is glucagon glucagon is putting the

brakes on this pathway and saying yo

chill we need to reverse this and make

energy available because blood glucose

is low so think about it guys

insulin will promote pfk to because it

will make fructose to 6 bisphosphate

which feeds back to PF k1 and makes this

happen faster but in another situation

glucagon will inhibit pfk too because PF

k2 would normally make fructose 2 6

bisphosphate which would feed back to PF

k1 and make this process happen faster

so again understanding the big picture

about what glycolysis is actually doing

helps you understand the regulatory

mechanisms that you need to memorize for

your test so the takeaway from this

slide is that PF k2 inhibited by

glucagon and promoted by insulin the

last enzyme that we need to talk about

is the enzyme that converts phospho enol

pyruvate to pyruvate the last step of

glycolysis that enzyme is pyruvate

kinase and just like pfk one this is

going to be inhibited by ATP and citrate

for the same exact reasons and those

reasons are again glycolysis wants to

create ATP glycolysis wants to make

pyruvate which can then become citrate

in the TCA cycle so therefore if you

already have ATP or you already have

citrate what's the point you don't need

to do glycolysis so the presence of

those products will inhibit the enzymes

that usually make like pollicis work so

guys that's it for glycolysis and you're

probably sitting there I started to have

a panic attack thinking about whoa whoa

dirty what about all the other enzymes

don't don't worry about the other

enzymes this is what you need to know

for USMLE and comlex you need to know

the enzymes I put in these slides the

regulatory mechanisms that I put in

these slides and understand the

difference between glucokinase and hexa

kinase that we discussed at the

beginning of this video all of the other

intermediary steps you don't need to

know them

you really don't they're not going to show

show

on your test unless you're taking a

college-level or intro to biochemistry

course you really don't need to know

them if you do want to know them for

completeness sake I would encourage you

to go online look at some diagrams

memorize some enzymes but this is what

you need to know to answer 99% of the

questions that'll show up on us Emily

complex your question banks your

practice tests etc so again and I cannot

stress this enough because it's the

biggest theme for all of biochemistry no

the rate-limiting enzyme no the

regulatory mechanisms and if you get

stuck on test day about what's

inhibiting or what's promoting ask

yourself what's the goal of this pathway

and therefore what do I think might

happen that's it if you liked this video

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YouTube Transcript:
Glycolysis