Glucose metabolism Flashcards
Enzymes found in the mouth
Salivary amylases and lingual lipases
No enzymes for protein breakdown
Enzymes found in the mouth
Salivary amylases and lingual lipases
No enzymes for protein breakdown
Elements that aid digestion in the stomach and their roles
Chief cells produce gastric lipase and pepsin
Gastrin stimulates both chief cells and parietal cells. Respond by secreting enzymes and HCl
Mechanical digestion occurs in stomach as well -> mechanical and chemical
Gizzard in birds is a special stomach part
Rudiments have specialized 3 parts that specialize in microbial digestion
Function of chief cells
Chief cells produce gastric lipase and pepsin
Function of HCl
Converts 3D protein structure to linear structure
Function of parietal cells
Produce HCl
Enzymes produced by pancreas
Trypsinogen,
Chymotrypsinogen
Carboxypeptidase A & B
Active enzymes target specific
Where does absorption of lipid soluble substances occur?
Stomach
In what form are enzymes secreted by pancreas into intestines
In an inactive form
How are inactive pancreatic enzymes activated
Activated by the acidic food
Where does most nutrient absorption occur?
Duodenum
1 step of glycolysis Reaction Purpose Enzyme Reaction type
Glucose+ ATP-> Glucose 6-phosphate + ADP +H
Hexokinase
Phosphoryl transfer
Traps glucose inside the cell- > lowers intracellular (unphosphorylated) glucose to allow further uptake
Irreversible
Reactions of the preparatory phase of glycolysis
Glucose-> glucose 6-phosphate-> fructose 6-phosphate-> fructose 1,6-bisphosphate-> Glyceraldehyde 3-phosphate and Dihydroxyacetone phosphate
Reactions of the payoff phase of glycolysis
(2) Glyceraldehyde 3-phosphate-> (2) 1,3-Bisphosphoglycerate-> (2) 3-Phosphoglycerate-> (2) 2-Phosphoglycerate-> (2) Phosphoenolpyruvate-> (2) Pyruvate
What is the 1st priming reaction?
Glucose-> glucose 6-phosphate
What is the 2nd priming reaction?
fructose 6-phosphate-> fructose 1,6-bisphosphate
What are the 2 ATP-forming reactions (substrate-level phosphorylation)
1,3-Bisphosphoglycerate-> 3-Phosphoglycerate
Phosphoenolpyruvate-> Pyruvate
What’s a tautomer?
Tautomers are isomers of a compound which differ only in the position of the protons and electrons.
Which glycolysis reaction involves tautomerization?
Phosphoenolpyruvate-> Pyruvate second ATP forming reaction
2 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
Glucose 6-phosphate fructose 6-phosphate
Phosphoglucose isomerase
Isomerization
- Makes next steps easier
- C1 of fructose is easier to phosphorylate by PFK
- allows for symmetrical cleavage by aldolase
- Reversible
3 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
fructose 6-phsophate-> fructose 1,6-bisphosphate
phosphofructokinase-1
- Generates a symmetric 6-carbon molecule
- First committed step of glycolysis
- This process uses the energy of ATP
- Irreversible
4 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
fructose 1,6-bisphosphate- > G3P + dihydroxyacetone phosphate
by aldolase
6-carbon sugar cleaved into two 3-carbon sugars
High-energy phosphate sugars
Reversible
5 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
Aldolase creates two triose phosphates:
dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP)
v Only GAP is the substrate for the next enzyme-> triose phosphate isomerase converts DHAP to G3P
v Completes preparatory phase of glycolysis
v Reversible
6 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
G3P-> 1,3-Bisphosphoglycerate glyceraldehyde 3-phosphate dehydrogenase Incorporates inorganic phosphate v First energy-rich molecule: Oxidation of GAP with NAD+ gives NADH v Reversible
7 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
1,3-Bisphosphoglycerate-> 3-Phosphoglycerate
by phosphoglycerate kinase
v Substrate-level phosphorylation to make ATP
v No oxidation required
v Quick source of ATP
v 1,3-bisphosphoglycerate donates the phosphate group to ADP to make ATP
v Reversible
8 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
3-Phosphoglycerate-> 2-Phosphoglycerate
by phosphoglycerate mutase
v Mutases catalyze the migration of functional groups
v Phosphohistidine of the enzyme donates its phosphate
to 3-phosphoglycerate at the 2-carbon before
retrieving phosphate from the 3-carbon
v Reversible
9 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
2-Phosphoglycerate-> Phosphoenolpyruvate
by enolase
Generates a high-energy phosphate compound
v Reversible
10 step of glycolysis Reaction Purpose Enzyme Reaction type Irreversible/reversible
Phosphoenolpyruvate-> pyruvate by pyruvate kinase Substrate-level phosphorylation v Pyruvate kinase requires metal ions for activity. v Irreversible
Which step is lysis step?
Fructose 1,6-bisphosphate -> G3P and Dihydroxyacetone phosphate
Which step is isomerization step?
Glucose 6-phosphate to Fructose 6-phosphate
Elements that aid digestion in the stomach and their roles
Chief cells Gastric lipase and pepsin HCl Gastrin stimulates both chief cells and parietal cells. Chief cells and parietal cells
Function of chief cells
Chief cells produce gastric lipase and pepsin
Function of HCl
Converts 3D protein structure to linear structure
Function of parietal cells
Produce HCl
Definition of Gluconeogenesis:
Glucose is formed from non-carbohydrate source
Free energy released in glycolysis is conserved as __ and __
Free energy released in glycolysis is conserved as ATP and NADH
Reactions of the preparatory phase of glycolysis
Glucose-> glucose 6-phosphate-> fructose 6-phosphate-> fructose 1,6-bisphosphate-> Glyceraldehyde 3-phosphate and Dihydroxyacetone phosphate
Reactions of the payoff phase of glycolysis
(2) Glyceraldehyde 3-phosphate-> (2) 1,3-Bisphosphoglycerate-> (2) 3-Phosphoglycerate-> (2) 2-Phosphoglycerate-> (2) Phosphoenolpyruvate-> (2) Pyruvate
What is the 1st priming reaction?
Glucose-> glucose 6-phosphate
What is the 2nd priming reaction?
fructose 6-phosphate-> fructose 1,6-bisphosphate
What are the 2 ATP-forming reactions (substrate-level phosphorylation)
1,3-Bisphosphoglycerate-> 3-Phosphoglycerate
Phosphoenolpyruvate-> Pyruvate
What’s a tautomer?
Tautomers are isomers of a compound which differ only in the position of the protons and electrons.
Which step is lysis step?
Fructose 1,6-bisphosphate -> G3P and Dihydroxyacetone phosphate
What is GAPDH used for? Why?
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) Is produced in such large quantities by the cells that it is used as a measurement control- highly expressed
What is used in glycolysis
glucose; 2 ATP; 2 NAD+; 4 ADP
What is made in glycolysis. What are the products used for?
– 2 pyruvate
• different fates
– 4 ATP (2 ATP net!)
• Used for energy-requiring processes within the cell
– 2 NADH
• Must be reoxidized to NAD+ in order for glycolysis to continue
Overall formula of glycolysis
1 Glucose + 2 ATP + 2 NAD+ + 4 ADP + 2 Pi = 2 Pyruvate + 2 NADH + 2 H+ + 2ATP + 2 H2O
What are the possible fates of glycolysis? Conditions and products
- Fermentation to ethanol in yeast in hypoxic or anaerobic conditions: 2 Pyruvate -> 2 ethanol + 2CO2
- In animals plants and any microbial cells in aerobic conditions 2 Pyruvate-> 2 Acetyl CoA-> Citric acid cycle-> 4CO2 + 4H2O
- Fermentation to lactate in muscles, erythrocytes, in some other cells and some microorganisms 2 Pyruvate -> 2 lactate in hypoxic or anaerobic conditions
Erythrocytes convert pyruvate to __
Erythrocytes convert pyruvate to lactate
What occurs to lactate in the liver
It gets converted to glucose
Through gluconeogenic pathway
Formula for pyruvate conversion into lactate
Pyruvate+ NADH -> lactate + NAD+
__% of gluconeogenesis occurs in the liver
80% of gluconeogenesis occurs in the liver
Why is pyruvate to lactate conversion so important?
Conversion of pyruvate to lactate is essential to generate NAD+ (electron acceptors) which is essential for glycolysis
What is cori cycle?
metabolic pathway in which lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, which then returns to the muscles and is metabolized
Various __ can be broken down to various intermediates for glycolysis
Various carbohydrates can be broken down to various intermediates for glycolysis
Various carbohydrates can be broken down to various intermediates for glycolysis. At which stages of glycolysis can they enter
As: glucose 1-phosphate glucose 6-phosphate fructose 6-phosphate fructose 1,6-bisphosphate glyceraldehyde 3-phosphate
What’s HIF
HIF (hypoxia inducible factor) is a transcription factor that is activated during hypoxia (hypo= low)
Has multiple isoforms
Hexokinase has multiple __
Hexokinase has multiple isoforms
What’s PHD and how does it function?
Normoxia- normal oxygen concentration - PHD (prolyl hydroxylase) is present
PHD2 (isoform of PHD) senses oxygen concentration in the environment
During normoxia PDH2 induces ubiquitination of HIF to degrade it as it is not needed during normal oxygen concentration
How does PHD2 and HIF function during hypoxia?
PHD2 doesn’t function as oxygen is low
HIF is not ubiquitinated and degraded- stabilization of HIF
HIF-1α dimerizes with HIF-1β They become a functional dimer
Dimer enters the nucleus and interacts with CBP. Together, they bind to hormone response elements (HRE) to regulate HIF target genes
What is special about
HIF has multiple isoforms: HIF-1a, HIF-1b
HIF-1a that is ubiquitinated and degraded
What’s CBP?
cAMP response element Binding Protein- is a transcription factor
It is a GPCR response activated transcription factor. It responds to cAMP-
What are the HIF target genes?
GLUT 1/3 Glycolytic enzymes: Hexokinase PFK Aldolase GAPDH Phosphoglycerate Kinase Phospohoglycerate Mutase Enolase Lactate dehydrogenase
How does the rate of HIF genes compare in hypoxic and normoxic conditions?
HIF genes are expressed in higher amounts in hypoxic conditions to allow glycolysis to happen at high pace to regenerate NAD+ as they code for glycolytic enzymes
During normal oxygenic conditions glycolytic enzymes don’t have to be synthesized in high amounts
What’s gluconeogenesis?
Synthesis of glucose from non-carbohydrate sources
Animals use/do not use fatty acids for gluconeogenesis
Animals do not use fatty acids for gluconeogenesis
Metabolism of fatty acids is called b-oxidation which yields Acetyl-CoA
Acetyl-CoA cannot be converted to glucose
Which tissues in the body rely heavily on glucose?
brain, RBC, testes, renal medulla, embryo)
Where does gluconeogenesis happens?
mainly liver; also renal cortex and intestinal epithelium
Recovery after vigorous exercise involves __
Recovery after vigorous exercise involves gluconeogenesis
Gluconeogenesis of lactate
Lactate-> pyruvate-> TCA-> Phosphoenolpyruvate-> G6P
Gluconeogenesis of AA
Glucogenic AA-> TCA-> Phosphoenolpyruvate-> G6P
Gluconeogenesis of triacylglycerols
triacylglycerols->glycerol -> g6p
Gluconeogenesis of CO2
CO2 fixation-> 3-phosphoglycerate -> G6P
How does gluconeogenesis differ from glycolysis?
Gluconeogenesis is pretty much glycolysis in reverse apart form 3 steps
4 enzymes replace irreversible enzymes of glycolysis for gluconeogenesis to take place
Additional ATPs are used
Number of ATP and NADH required to make 1 molecules of glucose by gluconeogenesis?
6 ATP
2 NADH
What are the 3 irreversible reactions of glycolysis?
1) the conversion of glucose to glucose 6-phosphate by hexokinase
2) the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate by phosphofructokinase-1
3) the conversion of phosphoenolpyruvate to pyruvate by pyruvate kinase
What is generated by the reactions that replace irreversible reaction of glycolysis in gluconeogenesis?
Inorganic phosphates
First step of gluconeogenesis
Location
Reactants/products
Special notes
First step of gluconeogenesis pyruvate + 2 ATP-> Oxaloacetate + 2 ADP
takes place in mitochondria- pyruvate has to be there
Where does gluconeogenesis occurs
Pyruvate to Oxaloacetate conversion stakes place in mitochondria
Oxaloacetate conversion to PEP can take place either in mitochondria or cytoplasm
The rest of gluconeogenesis takes place in the cytoplasm
Describe 1st set of irreversible enzymes of glycolysis that are replaced in gluconeogenesis
pyruvate carboxylase and PEP carboxykinase replace pyruvate kinase
Pyruvate carboxylase takes pyruvate in mitochondria and adds bicarbonate group to make oxaloacetate
Oxaloacetate is then converted to PEP
Pyruvate carboxylase uses ATP;
PEP carboxykinase uses GTP
In glycolysis PEP was converted to pyruvate by a single enzyme pyruvate kinase
How is pyruvate ends up in mitochondria for gluconeogenesis?
Pyruvate is transported from the cytosol into mitochondria or is generated from alanine within mitochondria by transamination, in which the a-amino group is transferred from alanine (leaving pyruvate) to an a-keto carboxylic acid
Describe 2nd set of irreversible enzymes of glycolysis that are replaced in gluconeogenesis
phosphofructokinase -1 is bypassed by fructose 1,6-bisphosphatase (FBPase-1) which removes one phosphate group of fructose 1,6-bisphospate making it fructose 6-phsophate
Describe 3rd set of irreversible enzymes of glycolysis that are replaced in gluconeogenesis
The third bypass is the final reaction of gluconeogenesis, the dephosphorylation of glucose 6-phosphate to yield glucose
In gluconeogenesis the reaction catalyzed by glucose 6-phosphatase does not require synthesis of ATP; it is a simple hydrolysis of a phosphate ester
In glycolysis hexokinase reaction would require phosphoryl group transfer from glucose 6-phosphate to ADP, forming ATP, an energetically unfavorable reaction
_ enzymes of glycolysis vs _ of gluconeogenesis
10 enzymes of glycolysis vs 11 of gluconeogenesis
How do AA contribute to gluconeogenesis?
Glycogenic AA contribute to gluconeogenesis through multiple end products e.g. pyruvate -many of them come from TCA as intermediates
These AA intermediates can lead up to pyruvate and thus to gluconeogenesis
Why can’t leucine and lysine contribute to gluconeogenesis?
Their end product is Acetyl-coA thus they cannot contribute to gluconeogenesis - go to ketogenic pathway instead
They are ketogenic AA
What are glucogenic AA precursors of? Why?
All these amino acids are precursors of blood glucose or liver glycogen, because they can be converted to pyruvate or citric acid cycle intermediates.
What’s the most common fate of G6P?
Glycolysis
In which cells in pentose phosphate pathway more common?
More common in highly proliferative cells, such as intestinal epithelium or cancer cells
More common in cells of FA biosynthesis
More common in cells of sterols (cholesterol and steroids) synthesis
More common in cells with oxidative stress
What are the 2 enzymes of pentose phosphate pathway and their roles?
GAPdh- G6P dehydrogenase- begins the process of pentose phosphate pathway by converting glucose-6-phosphate to 6-phosphogluconate
Phospho-pentose isomerase converts ribulose 5-phsophate to ribose 5-phsophate.
Reactions of these enzymes produce NADPH
What’s is Ribose 5-phosphate precursor for?
Ribose 5-phosphate is precursor for many biological molecules such as nucleotides, coenzymes, DNA and RNA
What is the purpose of oxidative phase of pentose phosphate?
Oxidative phase generates 2 NADPH. End products are important for gene expression and proliferation
G6P dehydrogenase and Phospho-pentose isomerase are part of this phase.
What are the steps of Oxidative phase of pentose phosphate pathway
Glucose 6-phosphate-> 6-Phosphogluconate-> Ribulose 5-phosphate-> ribose 5-phosphate
Which tissues are susceptible to oxidative damage? What is important for these cells?
- Tissues exposed to high O2 (cornea and RBC) and thus oxidative damage
- NADPH is important in these cells
What’s NADPH a source of?
Hydrogen
Why is NADPH important?
Many enzymes such as enzymes for sterol, fatty synthesis depend on NADPH as hydrogen source. They use reductive biosynthesis- synthesis of biomolecules using hydrogen. Thus NADPH is important in liver cells, mammary glands, adrenal glands etc
NADPH also acts as a hydrogen source for glutathione reductase which is important in oxidative stress- in cells as RBC and cornea- exposed to high levels of oxygen
Which tissues use NADPH as a hydrogen source for their synthesis?
FA synthesis in liver, kidney and lactating mammary gland
Cholesterol/steroid synthesis in liver, adrenal and gonads
Describe the chemistry behind oxidative stress
Whenever there’s high oxygen concentration, there’s a possibility of formation of superoxide - oxygen with extra electron (unstable)
This can be converted to hydrogen peroxide which can be broken down to hydroxyl free radical which can damage lipids, 3D structure of proteins and DNA
How can hydrogen peroxide created during oxidative stress be neutralized?
Hydrogen peroxide can be converted to water to prevent the damage. This is catalyzed by glutathione peroxidase which requires 2 H+ to add to H2O2.
H2O2+ 2H+-> 2H2O
what’s the hydrogen source for glutathione peroxidase
Hydrogen source of glutathione peroxidase is glutathione which is found in 2 forms: GSH (reduced form) and GSSG (oxidized form- no hydrogen to donate)
Hydrogen is gotten from GSH
How’s GSSG turned into GSH
Oxidized form GSSG requires hydrogen which is provided by NADPH via glutathione reductase to come back to reduced form
NADPH comes from pentose phosphate pathway
What are the 2 phases of ribose 5 phosphate pathway?
Non-oxidative and oxidative
What is the purpose of non-oxidative phase of pentose phosphate?
Non-oxidative phase regenerates G6P from R5P
Are any carbons added or removed in non-oxidative phase of pentose phosphate?
No
How are non-oxidative and oxidative phases of pentose phosphate connected?
Transketolases and Transaldolases of non-oxidative phase are involved in conversion of ribose 5-phospahte (end product of oxidative phase) to fructose 6-phophate and ultimately to glucose-6-phosphate
What are the steps of non-oxidative phase of pentose phosphate pathway?
Ribose 5-phosphate is converted to sedoheptulose 7-phosphate by transketolase
Sedoheptulose 7-phosphate is converted to fructose 6-phosphate by transaldolase
Fructose 6-phosphate is then converted to glucose 6-phosphate
Why is non-oxidative phase of pentose phosphate pathway so economic?
Non-oxidative is economic as it brings back glucose 6-phosphate - no new glucose is diverted towards this reaction.
Can ribose 5-phsophate be generated in absence of glucose
F-6-P and GAP can yield R-5-P without glucose 6-phosphate, thus ribose 5-phosphate can be generated even in absence of glucose
Transketolases and Transaldolases are highly expressed in _ cells
Transketolases and Transaldolases are highly expressed in cancer cells
What induces negative feedback on enzymes in pentose phosphate pathway?
NADPH
What determines whether G6P goes into glycolysis or pentose phosphate pathway?
G6P partitioning either through pentose phosphate or through glycolysis depends on cell’s needs
- If cell needs ATP- G6P goes through glycolysis
If cells are exposed do oxidative stress or they need a lot of nucleotide synthesis-> pentose phosphate pathway
What activated G6PD?
NADP+
