Glucose Metabolism Flashcards
What are the main functions of glucose as a fuel?
- Extracellular matrix and cell wall polysaccharides
- Storage as glycogen, starch, and sucrose
- Oxidized to Pyruvate via Glycolysis
- Oxidized to Ribose-5-phosphate via the Pentose Phosphate Pathway
What is glycolysis?
Glucose is degraded to yield pyruvate, which yields some energy
What is gluconeogenesis?
Glucose is formed from a non-carbohydrate source; mainly proteins
What is glycogenesis?
Glycogen is polymerized from glucose units
What is glycogenolysis?
Glycogen is degraded to glucose units
What is glycolysis also called? Why?
- EMP Pathway
- Because of the scientists: Euler-Meyerhof-Parnas
What was particular about the scientists Euler-Meyerhof-Parnas?
They were all Jewish scientists that practiced during the World Wars
In which mechanisms is DHAP located? (2) What can it become? Through what enzyme?
1) Glycolysis
- Triose phosphate isomerase
- Glyceraldehyde-3-phosphate
2) Fatty acid synthesis
- Glycerol-3-phosphate dehydrogenase
- Glycerol-3-phosphate
What does GAPDH stand for?
Glyceraldehyde-3-phosphate dehydrogenase
What does PEP stand for?
Phosphoenolpyruvate
Where does substrate-level phosphorylation occur in glycolysis?
- Pyruvate kinase
- Phosphoglycerate kinase
Where does tautomerization occur in glycolysis? What is it?
- Conversion of the double bond by exchanging electrons
- Pyruvate kinase
In glycolysis, why can phosphorylation only occur on C-6 in hexokinase?
Because C-1 is a carbonyl group and cannot be phosphorylated
What does phosphohexoisomerase do?
- Converts Glucose-6-phosphate to Fructose-6-phosphate
- Moves the double bond to C-2 so that C-1 can be phosphorylated and become Fructose-1,6-bisphosphate
How many carbons do DHAP and glyceraldehyde-3-phosphate contain?
3 carbons each
What is used in glycolysis?
- 1 Glucose
- 2 ATP
- 2 NAD+
- 4 ADP
What is made in glycolysis?
- 2 Pyruvate
- 4 ATP (but 2 net)
- 2 NADH
What must be done for glycolysis to continue?
NADH must be oxidized to NAD+ by fermentation
What can pyruvate generate under anaerobic conditions? (2)
1) Fermentation to 2 Ethanol and 2 CO2 in yeast
2) Fermentation to 2 Lactate
How is NAD+ generated in glycolysis?
By converting pyruvate to lactate through lactate dehydrogenase
What particular type of cells are capable of converting pyruvate to lactate? Why?
- Erythrocytes since they do not have a mitochondria
- They need NAD+ to continue glycolysis
Where is lactate converted to glucose?
In the liver
What does the Cori Cycle explain?
How glucose is metabolized in muscles and how lactate is generated
What are possible glucose sources that can enter glycolysis?
- Glucose
- Lactose
- Sucrose
- They can enter at various points
What happens in glycogenolysis? What enzyme is required? What does it yield?
- Glycogen phosphorylase
- Glucose is made from glycogen
- Glycogen is cleaved at its NON-reducing end
- Yields glucose-1-phosphate
Which tissues depend mainly on glucose?
Brain, RBC, testes, renal medulla, embryo
What causes pregnancy-induced insulin resistance?
The embryo depends heavily on glucose
What compounds are converted to what in gluconeogenesis?
- Formation of glucose from non-carbohydrate sources (pyruvate, glycerol, glucogenic AA)
What is the main site of gluconeogenesis? What are other sites?
- Main: Liver
- Also, renal cortex and intestinal epithelium
Recovery after vigorous exercise involves ________________
gluconeogenesis
Which four enzymes are different in gluconeogenesis? Why?
- To bypass non-reversible reactions in glycolysis
- Pyruvate carboxylase and PEP carboxykinase
- Fructose-1,6-biphosphoatase-1
- Glucose-6-phosphatase
Which enzyme in glycolysis do pyruvate carboxylase and PEP carboxykinase replace in gluconeogenesis?
Pyruvate kinase
Which enzyme in glycolysis does fructose-1,6-biphosphoatase-1 replace in gluconeogenesis?
Phosphofructokinase-1
Which enzyme in glycolysis does glucose-6-phosphatase replace in gluconeogenesis?
Hexokinase
Which enzyme does pyruvate carboxylase resemble?
ACC since it contains biotin and uses ATP
What are the two steps to convert phosphoenolpyruvate from pyruvate?
1) Pyruvate + Bicarbonate –> Oxaloacetate
2) Oxaloacetate –> Phosphoenolpyruvate
What enzyme is used to convert: Pyruvate + Bicarbonate –> Oxaloacetate? Where does it occur? What energy source does it use?
- Pyruvate carboxylase
- Mitochondria
- Uses ATP
What enzyme is used to convert: Oxaloacetate –> Phosphoenolpyruvate? Where does it occur? What energy source does it use?
- PEP carboxykinase
- Cytosol/Mitochondria
- Uses GTP
All the intermediates of __________ can enter gluconeogenesis
Intermediates of TCA
Different AA yield different products in gluconeogenesis. What kind of products?
Pyruvate, a-ketoglutarate, succinyl-CoA, fumarate, and oxaloacetate
Which AA are not glucogenic?
Leucine and Lysine
What are the two fates of Glucose-6-Phosphate?
- Glycolysis
- Pentose Phosphate Pathway
What is the Pentose Phosphate Pathway also called?
Hexose monophosphate pathway
What is the Pentose Phosphate Pathway more common in?
- Highly proliferative cells (ex: skin)
- Cells of FA biosynthesis
- Cells of sterol synthesis
- Cells with oxidative stress (RBCs)
G6P leads to intermediates in two ways in the Pentose Phosphate Pathway. What are they?
1) Oxidative phase:
- G6P –> Ribulose-5-phosphate
2) Non-oxidative phase:
- Ribulose-5-phosphate –> G6P
What is the most important enzyme of the Pentose Phosphate Pathway?
G6P dehydrogenase
What enzyme converts ribulose-5-phosphate to ribose-5-phosphate?
Phospho-pentose isomerase
What can ribose-5-phosphate become? What is its use?
- Nucleotides, coenzymes, DNA, RNA
- Proliferation and gene expression
Where does NADPH come from?
From the Pentose Phosphate Pathway
What are the functions of NADPH?
- FA synthesis in liver, kidney, and lactating mammary gland
- Cholesterol/steroid synthesis in liver, adrenal and gonads
- Alleviation of oxidative stress
What happens if hydrogen peroxide is not metabolized properly?
- It yields a hydroxyl free radical
- Dangerous for lipids, proteins, and DNA
How does NADPH alleviate oxidative stress?
- NADPH is converted to NADP+ through glutathione reductase
- Donates electrons and reduces GSSG to GSH
- GSH has two hydrogens, which can be donated to hydrogen peroxide to turn them into water
What is GSH? What is GSSG?
o GSH: reduced form of glutathione
o GSSG: oxidized form of glutathione
What is the function of the Non-Oxidative Phase of the Pentose Phosphate Pathway? When is it used?
- Regenerates G-6-P from R-5-P
* Used in tissues requiring more NADPH than R-5-P
What regulates the Pentose Phosphate Pathway?
Intermediates, such as NADPH
What does NADP+ do in terms of regulation of the pentose phosphate pathway? What does NADPH do in terms of regulation?
- NADP+ activates G6PD and the PPP
- NADPH inhibits G6PD and the PPP (negative feedback - glycolysis will predominate)
Why is glycolysis regulated?
To maintain constant ATP levels
Which three enzymes are regulated in glycolysis?
- Hexokinase
- PFK-1
- Pyruvate kinase
Which compounds regulate expression/function of glycolytic enzymes?
Glucagon, epinephrine, and insulin
How many isoforms does hexokinase have?
I to IV
What are isozymes?
Slight differences in AA sequences, which creates slight changes in their function
Hexokinase 4 is also called what?
Glucokinase
Hexokinase I and II are predominantly expressed where? What do they have a high affinity for?
- Muscle
- High affinity for glucose
As the glucose concentration increases, how does the activity of Hexokinase I and II change? What about Hexokinase IV?
I and II: increases dramatically
IV: does not increase as much, lower affinity for glucose
What are Hexokinase I and II allosterically inhibited by?
Glucose-6-phosphate, end-product of the reaction
Where is Hexokinase IV predominantly expressed? How is their affinity for glucose?
- Liver
- Low affinity for glucose
Why is the low affinity for glucose of Hexokinase IV idea?
Since it is expressed in the liver, which does not used glucose (sends it to other body parts)
Is Hexokinase IV inhibited by glucose-6-phosphate? What about Hexokinase I and II?
I and II: Yes
IV: No
In the _____, glucose escapes glycolysis through a specific regulatory protein called _____
liver
GKRP
How does glucose escape glycolysis in the liver at low concentrations?
GKRP binds to Hexokinase IV and translocates it into the nucleus, which is not a site of glycolysis
When glucose concentration is low, ________ promotes the association between GKRP and hexokinase IV, which is shuttled to the nucleus
fructose-6-phosphate
What are the three major sites of glycolysis and gluconeogenesis?
Liver, kidney, and epithelial cells
When is hexokinase IV utilized to generate energy through glycolysis?
When there is high blood glucose
In gluconeogenesis, what enzyme replaces hexokinase from glycolysis?
glucose-6-phosphatase
In gluconeogenesis, what enzyme replaces PFK-1 from glycolysis?
fructose 1,6-bisphosphatase-1 (FBPase-1)
In gluconeogenesis, what enzyme(s) replaces pyruvate kinase?
- Pyruvate carboxylase
- PEP carboxykinase
PFK-1 commits _____ to ______
glucose
glycolysis
What inhibits PFK-1?
- High ATP
- High citrate, which increases ATP-inhibition
What stimulates PFK-1?
- High ADP
- High AMP
What inhibits FBPase-1?
High AMP
What pathways does insulin promote?
- Glycolysis
- Glycogenesis
- TG synthesis
What pathway does glucagon inhibit? What does it stimulate?
- Inhibits glycolysis
- Stimulates gluconeogenesis
Is Fructose-2,6-bisphosphate used in glycolysis?
NO, it is just a regulator of the glycolytic pathway
What does F26BP activate? What does it inhibit?
- Activates PFK-1 (glycolysis)
- Inhibits FBPase-1 (gluconeogenesis)
Fructose 2,6-bisphosphate is synthesized from ________ by _____, which requires ____
Fructose 6-phosphate
PFK-2
ATP
Fructose 6-phosphate is synthesized from ___________ by __________, which does not require _____
Fructose 2,6-bisphophate
FBPase-2
ATP
Are PFK-1 and FBPase-1 located on the same protein?
No
Are PFK-2 and FBPase-2 located on the same protein?
Yes
FBPase-2 is activated when PFK-2 is (phosphorylated/dephosphorylated)
phosphorylated
What stimulates the phosphorylation of PFK-2?
Glucagon
An increase of FBPase-2 stimulates what?
Gluconeogenesis
Insulin causes (phosphorylation/dephosphorylation) of PFK-2 by stimulation what?
dephosphorylation
phosphoprotein phosphatase
An increase of PFK-2 stimulates what?
Glycolysis
Xylulose-5-phosphate is found where?
In the non-oxidative phase of the pentose phosphate pathway
What is the role of xylulose-5-phosphate? What does it stimulate/inhibit?
- Brings back glucose-6-phosphate to recycle glucose
- Stimulates glycolysis
- Inhibits gluconeogenesis
High amounts of Xylulose-5-phosphate are acquired when there are high amounts of ______
glucose
What inhibits pyruvate kinase?
- Pyruvate
- ATP
- Acetyl-CoA
- Long-chain fatty acids
What activates pyruvate kinase?
Fructose 1,6-bisphosphate
How is pyruvate kinase inactivated? Where does this occur?
- When it is phosphorylated
- ONLY occurs in the liver (muscle is not affected by PKA)
- PKA phosphorylates it
Pyruvate in the liver can undergo _________ to yield glucose, or _________ to yield energy
gluconeogenesis
TCA cycle
How can pyruvate in the liver go through gluconeogenesis?
Converted to oxaloacetate by pyruvate carboxylase
How can pyruvate in the liver go through the TCA cycle?
Converted to Acetyl-CoA by the pyruvate dehydrogenase complex
What does high Acetyl-CoA concentration activate and inhibit?
- Activates pyruvate carboxylase
- Inhibits the pyruvate dehydrogenase complex
How does a high amount of glucose contribute to an increase in FA synthesis?
- Glucose in PPP produces X-5-P
- X-5-P activates a phosphatase, which dephosphorylates ChREBP, which moves to the nucleus
- The dephosphorylation of ChREBP in the nucleus makes it mix with MLS
- Once the mixture binds to ChoRE, they promote mRNA synthesis for a specific gene, such as Pyruvate kinase, Acetyl-CoA carboxylase, FA synthase
How is FOXO1 inactivated? What happens?
- Inactivated when it is phosphorylated
- Forces it to remain in the cytoplasm, degradation through ubiquination
How is FOXO1 activated? What happens?
- Activated when it is dephosphorylated by phosphoprotein phosphatase
- Travels to the nucleus
In the nucleus, FOXO1 creates mRNA sequences for what? They are enzymes of what?
- PEP carboxykinase and glucose-6-phosphate
- Enzymes of gluconeogenesis
FOXO1 suppresses the transcription of enzymes of which pathways?
Glycolysis, PPP, and FA synthesis
What is the consequence of the fast multiplication of cancerous cells?
Oxygen cannot be provided quickly enough (hypoxia)
In cancer cells, proteins are involved in which pathways?
Glycolysis and PPP
What are the transcription factors called in cells exposed to hypoxia?
HIFI: Hypoxia-Inducible Factor 1
What does HIFI activate? What does it inhibit?
- Activates the enzymes of glycolysis
- Inhibits the enzymes that promote the synthesis of Acetyl-CoA
Why does HIFI inhibit Acetyl-CoA synthesis?
- Since the cells are exposed to hypoxia, they lack oxygen
- Acetyl-CoA is the precursor for the TCA cycle, which requires oxygen
Why does HIFI promote the PPP?
Since precursors for DNA and RNA are from the PPP
