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Flashcards in CARBS - important Reactions and Enzymes to memorize Deck (84):
1

Hexokinase and glucokinase are involved in what important reaction?

At the beginning of glycolysis, priming glucose. IRREVERSIBLE REACTION
* D-glucose --> Glucose-6-phosphate

2

What does the function of hexokinase or glucokinase result in?

*these are tissue specific glucose primer reactions (IRREVERSIBLE reactions)
*net negative of charge on glucose traps glucose in cell
*conservation of energy (mostly) as ATP is expended to make more ATP by making glucose available for glycolysis
*next enzyme in glycolysis pathway needs the phosphate to bind selectively

3

what are the important differences between hexokinase and glucokinase?

hexokinase
*present in all cells
*low km and super specific for sugars, but NOT specific for glucose
*inhibited by glucose-6-phosphate
glucokinase
*super specific for glucose
*liver and pancreatic beta-cells
*high km for glucose
*inhibited by fructose-6-P

4

what is NORMAL blood glucose concentration?

4-5mM
*multiply by 18 to get mg/dL
*72-90 md/dL

5

What reaction concerning fructose is super important to know (glycolysis)?

The SECOND ATP investment in the glycolysis pathway
*Fructose-6-P + ATP --> Fructose-1,6-bis-P + ADP
*enzyme = phosphofructokinase I

6

Phosphofructokinase I is important for what reaction?

The SECOND ATP investment in the glycolysis pathway
*Fructose-6-P + ATP --> Fructose-1,6-bis-P + ADP

7

what is the reaction that COMMITS the cell to glycolysis pathway?

*the IRREVERSIBLE ATP-investment in glycolysis of:
*Fructose-6-P + ATP --> Fructose-1,6-bis-P + ADP
*catalyzed by PFK1 = phosphofructokinase 1

8

What stimulates and inhibits PFK1?

*PFK1 = phosphofructokinase 1
*AMP = stimulates
*Fructose-2,6-bis-P is the MOST POTENT stimulator
*F26BP is made by PFK2
*ATP inhibits

9

how does cAMP play a role in PFK1 activity?

When cAMP is LOW (high insulin/glucagon ratio, or in a fed state) there is a preferential de-phosph of PFK2,
*de-phosph PFK2 is ACTIVE
*MORE F26BP generation
*since F26BP is the most potent stimulator of PFK1 then low cAMP is indirectly a reason for HIGH PFK1 activity
*this makes sense as cAMP is low when insulin is high and glucagon low, or when there is a need for glycolysis

10

PFK1 is pretty much regulated by PFK2. How?

Not directly, but indirectly.
*in high insulin, PFK2 is NOT phosphorylated
*de-phosph PFK2 is a kinase and it will make F26BP which is the most potent activator of PFK1, which in turn is the important enzyme for formation of F16BP, the committed reaction of glycolysis
*thus, when PFK2 is phosphorylated, glycolysis is inhibitied (PFK2 is a phosphatase when phosphorylated) and gluconeogenesis is promoted
*opposite is true for high insulin state

11

Why is glyceraldehyde-3-phosphate dehydrogenase an important enzyme to recognize?

*not for high regulation, but for the step it is involved in
*(2) glyceraldehyde-3-P + 2 NAD+ --> (2) 1,3-bisphosphoglycerate + 2 NADH
*you now have the first energy payoff of glycolysis!
*this is the first oxidation reaction in glycolysis
*NAD+ must be regenerated to continue (thus lactate production in mitochondria-less cells)

12

What is the first substrate-level phosphorylation reaction in glycolysis?

(2) 1,3-bisphosphoglycerate + 2 ADP --> (2) 3-phosphoglycerate + ATP
*at this point the net ATP is 0 because there were investment reactions before this
*2 ATP produced at this step
*catalyzed by phosphoglycerate kinase

13

When does glycolysis produce net positive ATP?

(2) phosphoenol pyruvate + 2 ADP ---> (2) pyruvate + 2 ATP
*last part of glycolysis cycle
*catalyzed by IMPORTANT enzyme = pyruvate kinase

14

Why is pyruvate kinase an important enzyme to recognize?

*involved in the first step in glycolysis that provides net + ATP
*this is actually the last step of glycolysis, that produces pyruvate
*super regulated b/c either glycolysis or gluconeogenesis
*also, pyruvate is super important hub for other reactions, so pay attention to what makes pyruvate or breaks it
*2nd reaction of substrate-level phosphorylation
*inhibited by phosophorylation (PKA)
*inhibited by alanine
*inhibited by ATP
*stimulated by de-phosphorylation
*stimulated by F16BP
*think insulin and glucagon messing with PKA for this one

15

When you see enzyme-linked hemolytic anemia you think what two deficiencies

*most common is G6PD
*second most common is pyruvate kinase deficiency
*this means that RBCs never get ATP net +, and since they don't have mitochondria, it's hard for them to get energy

16

Lactate dehydrogenase does what?

*it works BOTH directions for conversion of pyruvate to lactate
*uses CoA and CO2
*makes NAD toward lactate
*uses NAD to make NADH toward pyruvate

17

what is happening in the fed vs. fast state in terms of pyruvate handling?

Fed state - pyruvate is used to make other stuff, either fatty acid synthesis or amino acids
Fasting state - pyruvate is made into oxaloacetate and shoved down the TCA cycle

18

Why is the reaction catalyzed by the pyruvate dehydrogenase complex so very important for TCA cycle?

*this is the first step of feeding pyruvate into the TCA cycle
*it makes acetyl-CoA
*it takes place immediately after pyruvate is moved from the cytoplasm to the mitochondria
*dependent on several co-enzymes
*dependent on several vitamins

19

what vitamins are important for the pyruvate dehydrogenase complex?

Thiamine (vitamin B1) - TTP
Riboflavin (vitamin B2) - FAD
niacin - NAD
pantothenate coenzyme A

20

why is thiamine deficiency an example of important glucose handling?

thiamine, or vitamin B1, is super important for the pyruvate dehydrogenase complex to make acetyl-CoA to start the TCA cycle
*if there is little B1, then the brain has trouble with it's main energy producing pathway (oxidation of glucose with TCA and electron transport)
*thus, B1 deficiency presents as wernicke's encephalopathy b/c neurons are whiny when starved
*also can present with beriberi problems in the heart because the heart muscle also uses TCA cycle a ton

21

How is PDH complex regulated (fed vs. fasting)?

*activated when energy is low
*inhibited when energy is high
*NADH, ATP, Acetyl-CoA, Fatty acids all alosterically inhibit the complex
*fasting IN THE LIVER, pyruvate is shunted to the gluconeogenesis pathway by the work of pyruvate carboxylase, which is stimulated by acetyl-CoA presence
*essentially, IN THE LIVER, in a fasting state pyruvate is moved up the chain, not down
*insulin = dephosp state, induction
*glucacon = phosph state, inhibition
*increased clacium means incrased dephosp state as calcium stimulates phosphatase

22

In one turn of the TCA cycle, what leaves and what enters?

1 acetyl group (acetyl-CoA) - 2 carbons that enter
*2 CO2 will leave the cycle
*oxaloacetate is used, but regenerated, leading to no net change in this carbon skelaton

23

What is important about citrate synthase?

*this enzyme is involved in the combining of the 2C acetyl-CoA with the 4C oxalaloacetate into citrate
*irreversible
*citrate is an important allosteric regulator and hub for formation of fatty acids
*allosterically inhibits PFK1 (which is the rate-limiting step in glycolysis, so this is feedback inhibition at its finest)

24

The production of alpha-ketoglutarate is important why?

*catalyzed by isocitrate dehydrogenase
*first CO2 produced
*first NADH produced
*entry point for amino acids to start gluconeogenesis

25

alpha-ketoglutarate dehydrogenase is important why?

*catalyzes the production of succinyl CoA
*complex of enzymes similar to pyruvate dehydrogenase
*5 coenzymes are required
*2nd time for generation of CO2 and NADH
*entry point for amino acids with odd number of carbons

26

where in the TCA cycle do you see SLP?

SLP = substate level phosphorylation
*from succinyl CoA to succinate
*succinate thiokinase - aka - succinyl coa synthetase
*important reaction b/c GTP is formed by substrate level phosphorylation

27

where are all the TCA cycle enzymes?

In the mitochondrial matrix. There is direct interplay between the electron transport chain and the TCA cycle

28

the oxidation of succinate to fumarate is important. WHY?

*enzyme - succinate dehydrogenase
*production of FADH2 from FAD
*this goes immediately and directly into the electron transport chain
*FAD is enzyme bound and is the electron acceptor in this reaction

29

what two "end" products of the TCA cycle are involved in gluconeogenesis?

Malate and OAA (oxaloacetate)

30

Where does the third NADH get generated in the TCA cycle?

oxidation of malate to oxaloacetate
*enzyme - maltate dehydrogenase
*this reaction is important b/c of ties to gluconeogenesis and b/c of the NADH generation

31

Where is perhaps the most important regulation of the TCA cycle?

At the level of pyruvate dehydrogenase, and the production of acetyl coa from pyruvate to start the cycle
*once the cycle is on, it's on
*the cycle is allosterically regulated by all the products of the cycle, especially NADH
*remember that TCA cycle is the entry point for lots of amino acids for gluconeogenesis

32

Where else, besides pyruvate dehydrogenase, is the TCA cycle particularly regulated?

at the level of citrate
*this is where the cycle can break off and move towards fatty acid synthesis more than glucose breakdown

33

Fumarate as a TCA cycle intermediate is important why?

This is the entry point for amino acids out of the urea cycle

34

where do odd-carbon number amino acids enter the TCA cycle?

They enter as succinyl CoA

35

Where are the IV large protein complexes that facilitate the electron transport chain?

• In the inner mitochondrial membrane

36

What protein complexes in the electron transport chain establish a proton gradient?

• I, III, IV
• Pump H+ from mitochondrial matrix to inter-membranous space

37

What is complex V in the electron transport chain?

• ATP synthase

38

What are the substrates and products of oxidative phosphorylation?

• NADH, FADH2, O2, Pi and ADP are all substrates
• NAD, FAD, H2O and ATP are the products

39

What does oligomycin do?

• Inhibits the ATP generation through oxidative phosphorylation
• Build-up of NADH and FADH2 will lead to inhibit TCA cycle
• Cells rely on glycolysis for energy which is not enough, and that means high serum lactate levels

40

Brown adipose tissue helps heat the body during cold exposure. How does this tie to the electron transport chain?

• This tissue uses uncoupling proteins to keep the proton gradient in the inner membrane space from being coupled to ATP generation
• Thus, it induces the use of cellular injury to be wasted as heat

41

What molecule is the main feedback regulator of oxidative phosphorylation?

• ADP
• If it is high, increase flow
• If it is low, decrease flow

42

What is PGC1alpha?

• In talking about the link between obesity, mitochondrial disease and cell injury
• Peroxisome proliferater-activated receptor gamma co-activator-1-alpha
• One of the key molecular mediators of mitochondiral proliferation and recently has been investigated as a drug target to combat metabolic diseases

43

What precursors are involved in gluconeogenesis?



• NON-carbohydrate sources
• Gluconeogenesis is using other things besides carbs to make glucose for the brain when the stores are running out

44

What tissues or cells rely on glucose as their primary or sole source of energy?

• Brain, RBCs, renal medulla, sperm and embryonic tissues
• These need glucose as either their main source of energy or their ONLY source of energy (sperm or RBCs with no mitochondria)

45

When is gluconeogenesis taking place?

• Fasting, vigorous exercise, low carb/high protein diet
• OR under conditions of stress
• Counter-regulatory hormones are high and in states of insulin resistance and type 2 diabetes

46

What organs are able to perform gluconeogenesis?

• Liver is the most important
• Kidney can also participate, up to 20% in the prolonged fasting state

47

What are the three main sources of carbon skeletons for gluconeogenesis?

• Lactate, amino acids and glycerol
• Lactate from anaerobic glycolysis, converted back to pyruvate then up the chain
• Amino acids, particularly alanine and glutamine (easy to get back to pyruvate and alpha ketoglutarate
• Glycerol comes into glycolysis pathway and up

48

Do fatty acids contribute carbon to gluconeogenesis?

• NO. however, their oxidation is critical as it generates the ATP necessary for gluconeogenesis which is an energy requiring pathway

49

What is the Cori cycle?

• RBC specific
• Glucose to lactate (anaerobic glycolysis)
• Then lactate diffuses into blood stream, goes to liver, which gets reconverted to pyruvate to be used in gluconeogenesis path

50

Describe how pyruvate and alanine, when abundant, start the process of gluconeogenesis

• Bypass reaction of gluconeogenesis one
• Pyruvate, when abundant, brought across mitochondrial membrane by specific transporters into mitochondrial matrix
• Pyruvate carboxylase is attached to biotin
• Carbon dioxide is bonded to biotin (uses ATP)
• Carbon dioxide transferred from pyruvate carboxylase to pyruvate, causing oxaloacetate
• OAA can't get out into cytosol so it gets reduced to malate (needs NADH reduction)
• Malate is oxidized to OAA in the cytoplasm
• PEP carboxykinase will convert OAA to PEP (by getting the CO2 off)

51

How does biotin deficiency relate to gluconeogenesis?



• Leads to buildup of pyruvate and that is converted to lactic acid
• Leads to lactic acidosis

52

What role does malate dehydrogenase play in gluconeogenesis?

• This is a mitochondrial enzyme AND a cytoplasmic enzyme
• The mitochondrial one Catalyzes the conversion of oxaloacetate to malate (reduction)
• Used NADH
• Malate can leave mitochondria thorugh malate-alpha-ketoglutarate transporter
• The cytosolic malate dehydrogenase will reverse the reaction, forming OAA From malate

53

Pyruvate carboxylase is regulated by what molecule's presence?

• Acetyl coA is the positive effector
• This enzyme drives pyruvate into OAA to get out of the mitochondria (through malate intermediate)

54

What is special energetically about PEPCK's reaction?

• PEPCK - phosphoenol pyruvate carboxykinase is the enzyme that catalyzes the conversion of OAA to phosphoenolpyruvate
• OAA + GTP --> PEP + CO2 + GDP
• Gets rid of CO2 that was added to the pyruvate in the mitochondria
• This takes an ATP and a GTP, which comes from fax oxidation
○ Thus, how fatty acids don't contribute carbons but they do contribute ATP

55

What is the bypass reaction II in gluconeogensis?

• Conversion of F16BP to F6P
• Enzyme - F16BPase - fructose 1,6-bisphoshatase
• KEY STEP
• The reverse of the PFK-1 step in glycolysis
• Regulated by F26BP just like PFK-1, but in the opposite way/direction
• During high glucagon, AC is turned up
• Increased cAMP means increased PKA, which means increased phosphorylation and INHIBTION of PFK-2
• Inhibited (phosphorylated) PFK-2 will reduce F26BP which will lead to reduced action of PFK-1
• Instead, FBP-1 will work in the opposite direction

56

Many different amino acids are "glucogenic" what does that mean and are there other things besides amino acids that do the same thing?

• Glucogenic just means that these species can provide the carbon backbone for gluconeogenesis
• Glycerol, released from adipose tissue during the breakdown of triglyceride, can enter the glucoenogenic pathway at the level of glyceraldehyde 3 phosphate

57

What is the 3rd bypass reaction in gluconeogenesis?

• Bypass reaction III - conversion of glucose-6-phosphate to glucose
• G6P + H2O --> glucose + Pi
• Enzyme - glucose-6-phosphatase
• Bypasses hexokinase (or glucokinase) reaction in the glycolysis direction
• In the membrane of the ER in hepatocytes and kidney cells
○ Thus these are the two organs that can perform this function
• The reaction takes place in the ER lumen, but glucose has to move from cytoplasm to ER to cytoplasm

58

How does Von Gierke's disease relate to gluconeogenesis?

• AR disease
• Deficiency of G-6-Phosphatase in the liver
• Glycogen is normal but affected individuals have severe fasting hypoglycemia, ketosis, lactic acidosis, enlarged liver and kidneys
• Essentially they can't get their stored glucose to the market because their product is stuck with permanent magnet-child-lock-alarms

59

Describe the steps of gluconeogenesis from the mitochondrial matrix to the cytoplasm then finally to the blood for delivery to tissues (particularly the brain)

*in the mitochondrial matrix, increasing levels of pyruvate with concurrent acetyl-CoA presence will stimulate the first reaction
1) pyruvate carboxylase - catalyzes pyruvate into oxaloacetate using CO2 conjugated to biotin, USING an ATP molecule
2) OAA can't cross the mitochondrial membrane, so it is coverted to malate by MITOCHONDRIAL malate dehydrogenase - simply reduces (using NADH) OAA to malate
3) CYTOPLASMIC malate dehydrogenase will reverse the reduction, GENERATING NADH from malate to produce OAA
4) now that you have cytoplasmic OAA you need to kick it back up the glycolysis tree for the gluconeogenesis pathway and Phosphoenol pyruvate decarboxylase is the enzyme that uses GTP and knocks off the carbon dioxide, forming phosphoenol pyruvate (one step ABOVE pyruvate)
5) from here unimportant, reversible reactions move phosphoenol pyruvate up the chain until the F16BP step, which is bypassed by Fructose-1,6-bisphosphatase (bypassing the PFK1 step) making F6P
6) the final important step is liberating glucose for transport out of the cell into the bloodstream and that happens by Glucose-6-phosphatase IN THE LIVER AND KIDNEYS - these organs have this enzyme in the LUMEN of the ER, so the G6P has to get into the ER then glucose exported from the ER lumen

60

What are the three possible fates of Glucose once it is made into G6P in the cell?

• Glycolysis, glycogen syntheis or shunted to the pentose phosphate pathway to generate NADPH and ribose sugars
• When glucose-6-P is in excess over the amounts needed for glycolysis the other two pathways are active

61

Where is glycogen stored?




• Mostly in the liver and the muscle
• But remember, muscle (skelatal) glycogen is for muscle use only and is not able to be released into the blood for other tissues
• So, pretty much liver is the accessible glycogen storage organ

62

How do glucose units of glycogen enter the glycolytic pathway?

• Sequential action of 2 enzymes
• Glycogen phosphorylase
• phosphoglucomutase

63

How fast can the two different glycogen stores be depleted?

• Depends slightly on the person
• Muscle - in an hour or so of strenuous exercise
• Liver - 12-24 hours of fast

64

What two hormones tightly control the synthesis or breakdown of glycogen?

• Insulin and glucagon

65

What reaction does phosphoglucomutase catalyze?

• Enzyme - phosphoglucomutase
• G6P --> glucose-1-P
• First step of getting glucose ready to be UDP-glucose for storage in glycogen

66

While the step of putting UTP onto glucose is not important, adding UDP-glucose to the growing glycogen chain IS important. What enzyme does this?

• Enzyme - glycogen synthase with help from glycogenin
• The activated UDP-glucose is transferred to the hydroxyl group at a C-4 terminus of glycogen to form an alpha-1,4-glycosidic linkage
• In the elongation step, UDP is displaced and released
• KEY REGULATED STEP
• Glycogen synthase can add glucose residues only if the polysaccharide chain has been initiated and already contains more than 4 glucose residues
• Glycogenin is a protein that forms the initiating site for glycogen synthesis

67

You see glycogenin and you think?

• Obviously, glycogenesis, but more importantly, the inititiaing site for glycogen synthesis
• Glycogen synthetase needs a primer of at least 4 glucose molecules before more chain can be built

68

What's up with alpha-1,6 linkages?

• As opposed to alpha-1,4 linkages
• The 1,6 linkages are the branch points
• Branching is important for the solubility of glycogen, the speed at which glycogen is made and broken down, and inborn errors of the branching enzyme result in disease
• Glycogen synthase adds on glucose residues until about 11
• The branching enzyme initially takes 6 or 7 residues and adds them onto a 6 carbon of the chain
• This new branch point must be 4 residues away from the previous brach point for the enzyme to fit

69

What is the key regulated enzyme and important reaction of glycogenolysis?

• Enzyme - glycogen phosphorylase
• Glycogen (n residues) + Pi --> Glucose-1-P + Glycogen (n-1 residues)
• Some of the energy of the glycosidic bond is perserved in the G1P molecule
• From here phosphoglucomutase is an enzyme that catalyzes the reversible reaction of G-1-P to G-6-P
○ Concentration dependent though
• Then a debranching enzyme shifts a block of 3 glycosyl residues form one outer branch to the other and glycogen phosphorylase continues
○ Results in a single glucose residue attached at the 6 carbon in an alpha-1,6 linkage
○ Glucosidase hydrolyzes the last alpha-1,6 linkage to yield a free glucose molecule, which hexokinase makes into G6P
• Thus, the debranching enzyme makes the branched molecule into a more linear one, allowing the glycogen phosphorylase to chug along

70

What are the three steps of glycogen degradation?

• Release of glucose-1-P from glycogen
• Remodeling of the remaining glycogen to permit further degradation
• Conversion of glucose-1-P into glucose-6-P for further metabolism or export from the cell

71

What are the three enzymes critical to know for glycogenolysis (glycogen breakdown)?

• Glycogen phosphorylase
○ Catalyzes the cleavage of glycogen to glucose-1-P
○ The key regulated enzyme in glycogenolysis
• Debranching enzyme
• Phosphoglucomutase

72

Describe the general regulation of glycogen metabolism

• Both glycogen breakdown and synthesis are regulated by the insulin and glucagon hormones
• These regulate the activity of key enzymes through reversible phosphorylation, all through cAMP and PKA levels
• Glycogen synthase and glycogen phosphorylase are regulated reciprocally by allosteric interactions and reversible phosphorylation reactions
• The important things to watch out for are kinases, phosphatases, calcium, and enzyme inhibitors

73

In terms of phosphorylation, glucacon has what effect vs. insulin?

• In general, glucagon will increase phosphorylation, while insulin decreases it
• Insulin decreases AC, thus decreases cAMP, thus decreases PKA, thus decreasing phosphorylation
• Glucagon is the opposite

74

G6P has what effect on the glycogen storage/breakdown machinery?


• Allosteric modulator, makes the whole pathway choose a certain direction
• Inhibits the glycogen phosphorylase but activates glycogen synthase

75

In muscle, AMP and calcium do the same thing to glycogen. What is that?

• AMP is an allosteric modulator of glycogen phosphorylase, activating it and leading to increased glycogen breakdown
• Calcium has the same result, but more indirect and through the phosphorylation of glycogen phosphorylase by phosphorylase kinase (activated by Ca/CaM)

76

Calcium plays what role in glycogen metabolism?

• During muscle contraciton , membrane depolarization promotes calcium release
• Calcium binds to calmodulin and the complex activates a phosphorylase kinase which phosphorylates glycogen phosphorylase
• Phosphorylation of glycogen phosphorylase in muscle activates the enzyme and leads to glycogen degradation
○ Makes sense since with increased calcium, that means increased work of the muscle cell, which means increased metabolic demand

77

Describe how cAMP plays a role in glycogen degradation

• Epinephrine OR glucagon are the hormones that signal the need for glycogen degradation
• Affect phosphorylase kinase as well as glycogen phosphorylase
• Binding of the hormone activates PKA through increasing AC and cAMP
• PKA phosphorylates phosphorylase kinase
○ Phospho-phosphorylase kinase is ACTIVE (phosphorylase kinase a)
• PP1 = protein phosphase 1, can de-phosph and inactivate phosphorylase kinase
• PP1 is active in insulin signaling
• Glycogen phosphorylase is also activated by phosphorylation, and that phosphorylation happens from phosphorylase kinase
• Does PP1 also deactivate glycogen phosphorylase?

78

How does cAMP affect the INHIBITION of glycogen synthesis?


• Remember glycogen synthase is iACTIVE in the de-phosph form
• So, inhibiting the activation of phosphorylase kinase means glycogen synthase does not get phosphorylated and is therefore ACTIVE
• Fits with the insulin = dephosph paradigm
• Glycogen synthase is serially phosphorylated, and activation state corresponds to number of phosphorylations
• More phosphorylations, more inactivity
• PP1 is what dephosphorylates glycogen synthase and G6P is what allosterically activates PP1 dephosph of glycogen synthase
○ G6P binds glycogen synthase and makes it a better substrate, it doesn't directly bind PP1

79

When glucose levels return to normal, what happens to the active glycogen phosphorylase?

• G6P is the allosteric regulator here, and it will bind glycogen phosphorylase in a way that makes it a better substrate for PP1 action
• Thus, it will send the signal to be turned off by dephosphorylation when glucose levels are back to normal

80

The Pentose phosphate pathway can also be called what?

• Hexose monophosphate shunt

81

What does the pentose phosphate pathway do? Why does it exist?

• Produces NADPH for the biosynthesis of fatty acids and steroids
• Prominent in tissues such as mammary gland, adrenal cortex, liver and adipose tissues where fatty acid and steroid synthesis are common
• Also produces ribose-5-phosphate for synthesis of nucleotides
• Produces glycolytic intermediates
• Divided into oxidative and non-oxidative phases
• Oxidative - NADPH generating
• Non-oxidative - genearate ribose-5-phosphate and glycolytic intermediates
• All this happens in the cytosol

82

When you see G6PD, you think what?


• G6PD = glucose-6-phosphate dehydrogenase
• Super important enzyme for the pentose phosphate pathway
• Key, regulated enzyme and important reaction for this pathway
• G6PD catalyzes the first reaction in the PPP
• Committed and rate-limiting step
• Generates the first NADPH
• A later step is a dehydrogenation and decaroxylation step that produces another NADPH and a ribose-5-phosphate
• This is the step separated into oxidative and non-oxidative phases

83

What is the clinical correlation for G6PD?

• A deficiency in this enzyme results in hemolysis
• The oxidative phase of the PPP is the major source of NADPH
• This provides the reducing equivalent for oxidation-reduction reactions particulary in those using GSH
• NADPH maintains glutathione in a reduced state
• Certain compounds like sulfa antibiotics, antimalarial drugs and fava beans react with GSH and deplete it
• G6PD deficiency people can't regenerate GSH to guard against ROS and hemoglobin becomes oxidezed
• Oxidized hemoglobin creates Heinz bodies, or insoluble aggregates
• These make the RBC membrane rigid and lead to RBC destruction and hemolytic anemia

84

What step of the PPP will set up the oxidative vs. non-oxidative phases?

• G6PD step
• G6PD = glucose-6-phosphate dehydrogenase
• Oxidative - generates the NADPH necessary for lipid biosynthesis
○ Important in tissues that make fatty acids and steroids
• Non-oxidative
○ Consists of a series of rearrangements and transfer reactions which convert ribulose-5-phosphate to ribose-5-phosphate for nucleotide synthesis