0:01 welcome back to the high-yield
0:04 biochemistry series this is brought to
0:07 you by dirty medicine in today's video
0:08 we're going to continue our discussion
0:11 about the biochemical pathways and talk
0:14 about glycolysis glycolysis is typically
0:16 the first biochemical pathway that you
0:18 learned when you're learning about
0:20 biochemistry and it's because of that
0:23 that it's extremely high yield shows up
0:26 on exams all of the time now when you're
0:29 learning about glycolysis as you'll see
0:31 me mentioned throughout this video it's
0:34 really important to remember the bigger
0:35 picture and when I say that I'm
0:37 referring to things like what is the
0:40 function of the role of glycolysis what
0:44 are we taking as a reactant and turning
0:46 into a product and what are the
0:48 regulatory mechanisms in terms of
0:51 feedback so what makes this go forward
0:53 what inhibits this and what is the
0:55 rate-limiting enzyme just like all of
0:57 the biochemistry videos that I've
0:59 created you need to know the
1:01 rate-limiting enzyme and the regulatory
1:03 mechanisms so we're talking about things
1:07 like inhibitors etc so let's start with
1:09 a quick overview of glycolysis
1:11 glycolysis is an irreversible
1:14 biochemical reaction that occurs in the
1:17 cytoplasm the net equation for
1:19 glycolysis is that you start with
1:21 glucose and the goal is to take that
1:24 glucose and turn it into pyruvate where
1:27 it can downstream take multiple pathways
1:30 through that pyruvate pathway and
1:33 preferentially usually this goes into
1:36 the citric acid cycle but here's the net
1:38 equation you've - you start with glucose
1:41 and you add two phosphates two ATP's and
1:45 two and a DS and what you get out of
1:48 that is two pyruvates plus two ATP's
1:54 plus 2 NADH plus two hydrogen's plus two
1:57 waters but if you wanted to just think
1:59 very simply about what glycolysis is
2:02 doing it's taking glucose and breaking
2:05 that glucose down into storable products
2:07 that the body can use in other
2:10 biochemical pathways so now that we've
2:12 understood the overview of glycolysis
2:13 let's just get
2:15 to the the meat and potatoes here we're
2:17 gonna talk about the pathway you need to
2:19 understand the pathway and I'm gonna pay
2:22 very special attention to the regulatory
2:24 mechanisms of this pathway and the
2:26 rate-limiting enzyme so you start with
2:29 glucose right any person takes a bite of
2:31 a cheeseburger eats a french fry drinks
2:33 a milkshake and they've got a bunch of
2:36 carbohydrate in their body and that
2:40 carbohydrate is composed usually of
2:41 glucose and if it's not of glucose then
2:43 the other types of sugars will get
2:44 turned into glucose
2:47 so that glycolysis can utilize it the
2:49 first step is glucose will get turned
2:52 into glucose 6-phosphate glucose
2:55 6-phosphate will get turned into
2:58 fructose 6-phosphate fructose
3:00 6-phosphate will get turned into
3:04 fructose 1 6 bisphosphate and now you've
3:06 got like multiple steps that are gonna
3:08 happen there's gonna be four or five
3:10 more reactions in this pathway and
3:13 you'll end up with phosphoenolpyruvate
3:16 which will get turned into pyruvate and
3:19 going from glucose down to pyruvate is
3:22 the entire glycolysis pathway so when
3:24 you get to pyruvate you're basically
3:26 finished with glycolysis now let's talk
3:28 about the important enzymes that you
3:30 need to know so the first step that
3:32 converts glucose to glucose 6-phosphate
3:34 there's actually two different enzymes
3:37 that can be used depending on the
3:38 circumstances of the glucose
3:41 concentration and where in the body
3:43 we're talking about so those two enzymes
3:47 are glucokinase and hexokinase so to be
3:50 perfectly clear either glucokinase or
3:53 hexokinase can convert glucose to
3:56 glucose 6-phosphate and what you'll need
3:57 to know for test a that's really high
3:59 yield is to understand under which
4:02 circumstances both of these enzymes
4:03 might be used
4:06 so for gluco kinase this enzyme has a
4:10 low affinity and a high km just remember
4:11 the reciprocal relationship between
4:14 affinity and km the higher the km the
4:16 lower the enzyme has an affinity for its
4:19 substrate so glucokinase has a low
4:20 affinity for glucose it typically
4:23 doesn't want to go and grab glucose and
4:24 the reason for this is because
4:27 glucokinase acts as a glucose
4:30 sensor its present in the liver and the
4:32 pancreatic beta-cells and it's only used
4:35 when glucose is at high concentrations
4:38 so basically what you should think of
4:40 glucokinase s is an emergency enzyme
4:43 that is acting as a glucose sensor and
4:45 it's really not grabbing glucose because
4:47 instead of grabbing glucose and breaking
4:49 it down through glycolysis what it's
4:51 doing is it's sensing glucose and it's
4:52 going okay let's test how much glucose
4:55 is over here and that's okay we're not
4:57 gonna jump in yet
4:59 HECO kinase you go first so hexokinase
5:02 on the other hand that is a high
5:04 affinity enzyme which means it has a low
5:06 km and because it has high affinity for
5:08 its substrate hexo kinase is the one
5:10 that's constantly going to be latching
5:12 on to glucose and converting it to
5:14 glucose 6-phosphate and sending it down
5:17 the glycolysis pathway and the reason
5:19 for that is because hexo kinase is the
5:21 enzyme that's used to operate the basal
5:24 glucose metabolism so constantly
5:26 throughout your body in all of your
5:28 tissues you have this enzyme hexokinase
5:31 that's just keeping a basal level of
5:33 glucose metabolism present it's trying
5:35 to make sure that your glucose level is
5:38 adequate throughout the body in all of
5:41 the tissues but if hexokinase becomes
5:43 overwhelmed because suddenly there's a
5:46 massive influx of glucose that is when
5:48 hexa kinase turns to glucokinase and
5:51 says gluco i know you usually have a low
5:52 affinity but i really need some help now
5:54 because the glucose concentration is
5:57 high so if you think about it that's the
5:59 reason that glucokinase is only found in
6:01 the liver and the pancreatic beta-cells
6:03 because it does a very specific
6:06 regulatory job where it's only acting
6:09 when the blood glucose levels are super
6:11 super high when that concentration
6:13 reaches some critical point that's when
6:15 glucokinase in the liver and the
6:16 pancreatic beta-cells
6:19 jumps in to save hexokinase so the
6:21 takeaway from this slide is that both
6:23 glucokinase and hexokinase are enzymes
6:26 that catalyze that conversion from
6:28 glucose to glucose 6-phosphate the only
6:30 difference is that hexokinase is kind of
6:32 there all of the time making a basal
6:35 level of glucose and glucokinase jumps
6:37 in in emergencies but understand the
6:39 differences between those two enzymes
6:41 that I've put in the gray boxes they are
6:43 extremely high yield and probably will
6:45 show up on your test so here's where we
6:47 are we've we've talked about the enzymes
6:49 in the first step the enzyme that
6:51 converts fructose 6-phosphate to
6:54 fructose 1 6 bisphosphate is the
6:57 rate-limiting enzyme of glycolysis and
6:59 that's phosphofructokinase 1 sometimes
7:02 you'll hear this referred to as PF K 1
7:06 so PF k 1 or phosphofructokinase 1 is
7:08 the rate-limiting enzyme and it converts
7:10 fructose 6-phosphate to fructose 1 6
7:13 bisphosphate now I told you at the start
7:15 of this video that the very important
7:17 thing to keep in mind for USMLE and
7:20 comlex is the regulatory mechanisms and
7:22 what I mean when I say regulatory
7:25 mechanisms are what inhibits this
7:27 pathway and what promotes this pathway
7:29 and we're going to talk about that for
7:31 the first time right here and because
7:34 phosphofructokinase 1 is the
7:36 rate-limiting enzyme it's really high
7:38 yield to understand what inhibits
7:41 phosphofructokinase 1 and what promotes
7:44 phosphofructokinase 1 and that's what
7:47 you see here so ATP and citrate will
7:50 inhibit the rate-limiting enzyme pfk one
7:54 but a MP will promote the rate-limiting
7:57 enzyme of pfk 1 and this should be
7:59 somewhat intuitive to you so so think
8:02 about what glycolysis is doing the role
8:05 of glycolysis is to take glucose convert
8:09 it to pyruvate and ATP and then let that
8:11 pyruvate enter one of many different
8:14 pathways but usually the citric acid
8:16 cycle where you'll then create citrate
8:19 so if you think about that the question
8:22 becomes what would this pathway want to
8:25 do if it already had ATP and therefore
8:28 didn't need to make it or if it already
8:30 had citrate and therefore didn't need to
8:32 make pyruvate which would then go to
8:35 citrate and that's why ATP and citrate
8:38 inhibit pfk one because if you have ATP
8:41 and you already have citrate then you
8:43 don't need to do glycolysis so the
8:45 presence of those products will inhibit
8:48 the rate-limiting enzyme and therefore
8:51 glycolysis won't occur now likewise
8:54 think about AM P if you have AM
8:58 which is mono phosphate only one you
9:00 don't have ATP and therefore if you
9:03 don't have ATP you want to do glycolysis
9:06 so in the presence of a MP which is to
9:09 say in a situation where you don't have
9:13 ATP a MP will promote PF k1 and will
9:16 therefore promote glycolysis so anytime
9:18 you're not really sure about how the
9:20 regulatory mechanisms are working think
9:22 about this intuitively ask yourself on
9:25 test say well would glycolysis happen if
9:27 there was a MP would glycolysis happen
9:29 if there was citrate it should make
9:31 sense to you if you understand what the
9:34 big picture role of these pathways are
9:37 so that's what promotes and inhibits pfk
9:40 one now I need to pause for a second and
9:41 tell you about this little nuance of
9:45 glycolysis so fructose 6-phosphate can
9:47 can go to fructose 1 6 bisphosphate as
9:50 you see on this slide but additionally
9:52 there's sort of a side step that occurs
9:55 a pivot if you will fructose 6-phosphate
9:58 can also become fructose 2 6
10:02 bisphosphate and if fructose 6-phosphate
10:05 will become fructose 2 6 bisphosphate
10:07 the enzyme that catalyzes this
10:11 conversion is phosphofructokinase 2 pfk
10:15 2 so very similarly named of course to
10:16 the rate-limiting enzyme that we just
10:19 talked about but instead of one it's two
10:22 so when this happens you create fructose
10:25 2 6 bisphosphate and interestingly that
10:29 fructose 2 6 bisphosphate will promote
10:33 pfk 1 so the goal when the body does
10:36 this is to make glycolysis happen faster
10:39 now the question then becomes what is
10:41 promoting or inhibiting
10:44 phosphofructokinase 2 or pfk 2 and
10:46 that's really simple so it's gonna be
10:49 inhibited by glucagon and it's gonna be
10:52 promoted by insulin so think about it if
10:54 fructose 2 6 bisphosphate makes
10:58 glycolysis happen faster and in
11:01 glycolysis you're breaking down glucose
11:04 it makes sense that insulin will promote
11:07 pfk 2 because in the presence of glucose the
11:08 the
11:09 body's gonna secrete insulin and the
11:12 body's telling anything that any cell
11:14 that has a glycolysis pathway occurring
11:16 it's like yo take that glucose break it
11:18 down please get this out of the system
11:21 and that's insulins roll the opposite of
11:23 that is glucagon glucagon is putting the
11:24 brakes on this pathway and saying yo
11:27 chill we need to reverse this and make
11:29 energy available because blood glucose
11:32 is low so think about it guys
11:35 insulin will promote pfk to because it
11:37 will make fructose to 6 bisphosphate
11:40 which feeds back to PF k1 and makes this
11:43 happen faster but in another situation
11:47 glucagon will inhibit pfk too because PF
11:49 k2 would normally make fructose 2 6
11:51 bisphosphate which would feed back to PF
11:54 k1 and make this process happen faster
11:57 so again understanding the big picture
11:59 about what glycolysis is actually doing
12:01 helps you understand the regulatory
12:03 mechanisms that you need to memorize for
12:06 your test so the takeaway from this
12:09 slide is that PF k2 inhibited by
12:12 glucagon and promoted by insulin the
12:13 last enzyme that we need to talk about
12:15 is the enzyme that converts phospho enol
12:18 pyruvate to pyruvate the last step of
12:21 glycolysis that enzyme is pyruvate
12:26 kinase and just like pfk one this is
12:29 going to be inhibited by ATP and citrate
12:31 for the same exact reasons and those
12:33 reasons are again glycolysis wants to
12:36 create ATP glycolysis wants to make
12:38 pyruvate which can then become citrate
12:41 in the TCA cycle so therefore if you
12:43 already have ATP or you already have
12:45 citrate what's the point you don't need
12:47 to do glycolysis so the presence of
12:50 those products will inhibit the enzymes
12:53 that usually make like pollicis work so
12:55 guys that's it for glycolysis and you're
12:56 probably sitting there I started to have
12:58 a panic attack thinking about whoa whoa
13:00 dirty what about all the other enzymes
13:02 don't don't worry about the other
13:03 enzymes this is what you need to know
13:06 for USMLE and comlex you need to know
13:08 the enzymes I put in these slides the
13:10 regulatory mechanisms that I put in
13:12 these slides and understand the
13:14 difference between glucokinase and hexa
13:15 kinase that we discussed at the
13:18 beginning of this video all of the other
13:19 intermediary steps you don't need to
13:20 know them
13:21 you really don't they're not going to show
13:21 show
13:23 on your test unless you're taking a
13:25 college-level or intro to biochemistry
13:27 course you really don't need to know
13:28 them if you do want to know them for
13:30 completeness sake I would encourage you
13:32 to go online look at some diagrams
13:35 memorize some enzymes but this is what
13:37 you need to know to answer 99% of the
13:39 questions that'll show up on us Emily
13:41 complex your question banks your
13:45 practice tests etc so again and I cannot
13:47 stress this enough because it's the
13:49 biggest theme for all of biochemistry no
13:51 the rate-limiting enzyme no the
13:53 regulatory mechanisms and if you get
13:55 stuck on test day about what's
13:56 inhibiting or what's promoting ask
13:59 yourself what's the goal of this pathway
14:01 and therefore what do I think might
14:03 happen that's it if you liked this video
14:05 drop me a like or a comment in the
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