Regulation of Metabolism Flashcards
Which pathway(s) can be involved in increasing blood glucose concentrations? (There may be more than one answer)
a) Glycolysis
b) Glycogenesis
c) Gluconeogenesis
d) Glycogenolysis
c & d
What is the pathway responsible for converting glucose into pyruvate called?
Glycolysis
What is the pathway responsible for converting pyruvate into glucose called?
Gluconeogenesis
What is the pathway responsible for converting glucose into glycogen called?
Glycogenesis
What is the pathway responsible for converting glycogen into glucose called?
Glycogenolysis
How many steps does glycolysis consist of?
10 steps
What does the preparatory phase of glycolysis involve?
The phosphorylation of a molecule of glucose and it’s conversion into two molecules of Glyceraldehyde-3-phosphate
How many molecules of ATP are used in the preparatory phase of glycolysis?
2
What does the payoff phase of glycolysis involve?
The conversion of both molecules of glyceraldehyde-3-phosphate into two molecule of pyruvate
How many ATP and NADH molecules are released in the payoff phase of glycolysis?
4 ATP
2 NADH
What is the overall reaction of glycolysis?
Glucose + 2NAD+ + 2ADP + 2Pi -> 2Pyruvate + 2NADH + 2H+ + 2ATP
Under what conditions is the pathway of glycolysis active?
ATP is low
ADP is high
NADH to NAD+ ratio is low
AMP is relatively high
Where does gluconeogenesis primarily occur?
Liver cells
How many reactions in the glycolytic pathway are reversible?
7
What is the overall reaction of gluconeogenesis?
2Pyruvate + 4ATP + 2GTP + 2NADH + 2H+ + 4H2O -> Glucose + 4ADP + 2GDP + 6Pi + 2NAD+
Why are some of the enzymatic reactions in the pathways of glycolysis and gluconeogenesis irreversible under normal physiological conditions?
They have very high ΔG values
Under what conditions would gluconeogenesis be active in the liver?
When glycogen stores start to deplete such as during an overnight fast
What is the 1st futile cycle?
The first step of glycolysis and the last step of gluconeogenesis where glucose is converted into glucose-6-phosphate (and vice versa)
Which enzyme is required to convert glucose into glucose-6-phosphate in glycolysis?
Hexokinase
What enzyme is required to convert glucose-6-phosphate into glucose in gluconeogenesis?
Glucose-6-phosphatase
Where is hexokinase found?
In all cells which have the glycolytic pathway
Where is glucose-6-phosphatase found?
Hepatocytes (liver cells)
What type of hexokinase is found in liver cells?
Hexokinase IV
What type of hexokinase is found in muscle cells?
Hexokinase I and II
Which has a higher affinity (lower Km) for glucose: muscle hexokinase or liver hexokinase?
Muscle hexokinases
What is the other name for glucokinase?
Hexokinase IV
Why is it important for the hexokinase in the liver to have a high Km?
This hexokinase requires a high concentration of glucose in order for the reaction to take place. This means that glucose isn’t used up in the liver when the blood-glucose concentration is low
What happens to glucose in the liver when the blood-glucose levels are low?
The glucose produced in the liver by gluconeogenesis will not undergo glycolysis because the hexokinase has a high Km, therefore it will leave the liver cells and increase the blood-glucose concentration
Which isozymes of hexokinase is not inhibited by G-6-P?
Hexokinase IV
What is the 2nd futile cycle?
The conversion of Fructose-6-phosphate into fructose-1,6-bisphosphate and the reverse reaction in gluconeogenesis
What enzyme is responsible for converting fructose-6-phosphate into fructose-1,6-bisphosphate in glycolysis?
Phosphofructokinase-1 (PFK-1)
What enzyme is responsible for converting fructose-1,6-bisphosphate into fructose-6-phosphate in gluconeogenesis?
Fructose 1,6, bisphosphatase-1 (FBP-1)
True or False:
PFK-1 has both substrate-binding and regulator-binding sites
True
Is ATP an activator or inhibitor of PFK-1?
Inhibitor
How does citrate effect PFK-1?
Citrate is a key intermediate in aerobic metabolism and an allosteric regulator of PFK-1. High concentrations of citrate increases the inhibitory action of ATP and signals the cell that it is meeting current energy needs
Is ATP an activator or inhibitor of fructose 1,6 bisphosphatase?
Inhibitor
What hormone is secreted when blood-glucose levels drop?
Glucagon
What effects does glucagon have?
- Activates gluconeogenesis in the liver
- Causes the breakdown of glycogen
Both cause an increase in blood-glucose levels
What hormone is released when blood-glucose levels are high?
Insulin
How does Fructose-2,6-bisphosphate effect the enzymes in the 2nd futile cycle?
Activates PFK-1 and inhibits FBPase-1
Which enzyme catalyses the conversion of fructose-6-phosphate into fructose-2,6-bisphosphate?
PFK-2
Which enzyme catalyses the conversion of fructose-2,6-bisphosphate into fructose-6-phosphate?
FBPase-2
What controls the activity of PFK-2 and FBPase-2?
Insulin activates PFK-2 and glucagon activates FBPase-2
What is the 3rd futile cycle?
The conversion of 2-phosphoenol-pyruvate into pyruvate in glycolysis and the reverse reaction in gluconeogenesis
What is the enzyme that catalyses the conversion of 2-phosphoenol-pyruvate into pyruvate?
Pyruvate kinase
How many reactions are required to convert pyruvate into 2-phosphoenol-pyruvate?
2
What is the intermediate of the conversion of pyruvate into 2-phosphoenol-pyruvate?
Oxaloacetate
What enzyme is required to convert pyruvate into oxaloacetate?
Pyruvate carboxylase
What enzyme is required to convert oxaloacetate into 2-phosphoenol-pyruvate?
Phosphenol pyruvate carboxylase
How many isozymes of pyruvate kinase are there?
3
What are inhibitors of pyruvate kinase?
ATP
Acetyl CoA
Long chain fatty acids
What activates pyruvate kinase?
Fructose-1,6-bisphosphate
How does glucagon effect pyruvate kinase?
Glucagon increases the levels of cyclic AMP (cAMP) which activates the cAMP-dependent protein kinase. This phosphorylates and inactivates the liver isoforms of pyruvate kinase and causes the liver cells to consumer less glucose
How does epinephrine effect pyruvate kinase?
Epinephrin causes an increase of cAMP in the muscles which activates glycolysis
What are the two ways pyrimidines are synthesised?
De novo synthesis
Salvage pathways
What is de novo synthesis?
Synthesis of pyrimidines from small precursors (amino acids, PRPP, CO2, formate) where the free bases are not intermediates. The pyrimidine ring is synthesised as orotate, attached to ribose then converted
What is the salvage pathways?
synthesis of pyrimidines from nucleosides or bases from the diet or nucleic acid breakdown
What is the enzyme responsible for converting ribonucleotides into deoxyribonucleotides?
Ribonucleotude reductase
How are purines synthesised?
De novo synthesis
Salvage pathway
What are the characteristics of the de novo purine synthesis?
- Free bases are not intermediates
- The purine ring structure is built onto phosphoribosyl pyrophosphate (PRPP) in 11 steps to give the precursor purine inosinate (IMP)
- The atoms of the purine ring are contributed by a number of compounds, including amino acids (aspartic acid, glycine and glutamine), CO2 and folate derivatives
- Inosinate (IMP) is the first intermediate to have a complete purine ring
- IMP is then converted to AMP and GMP
What is produced when purines are degraded?
Uric acid
Which molecules act has inhibitors in the regulation of purine synthesis?
IMP
AMP
GMP
Which enzyme allows cell to reuse degraded guanine?
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
Which enzyme allows cells to reuse degraded adenine?
Adenine phosphoribosyltransferase
What conditions are caused by abnormal purine metabolism?
Gout, SCID and Lesch-Nyhan Syndrome
What is the defect and symptoms of Gout?
Defect: Enzymes of purine breakdown
Symptoms: High uric acid and arthritus
What is the defect and symptoms of SCID?
Defect: ADA deficiency
Symptoms: High dATP, loss of T and B cells and immune deficiency
What is the defect and symptoms of Lesch-Nyhan Syndrome?
Defect: HGPRT deficiency
Symptoms: High PRPP and Uric Acid, Gout, Brain Damage and Self-mutilation
What are the largest family of cell surface receptors?
G-protein coupled receptors (GPCRs)
How many transmembrane segments does a GPCR have?
7
What signalling molcules are recognised by GPCRs?
Hormones, neurotransmitters and peptides
What happens when a GPCR is activated?
Binding of a ligand to its specific receptor induces a conformational change in a GPCR triggering the activation of its associated G protein
What is the structure of a G-protein?
This G protein is a trimeric, GTP-binding protein consisting of an α, β and γ subunits. The α and γ subunit each have lipid tails that allow them to remain anchored to the cell membrane.
What is the state of the α subunit in its inactive form?
In its inactive form, the α subunit of the trimeric G protein is bound to guanosine diphosphate (GDP)
What happens to the subunits when the G-protein is activated?
When activated, GDP is released and the α subunit quickly binds a molecule of guanosine diphosphate (GTP). This subsequently triggers the release of the α subunit from both the receptor and the β/γ subunits which are also now active yet remain bound to each other. The active subunits then act on target proteins that stimulate second messengers
What is Chronic Myeloid Leukaemia (CML)?
Overproduction of white blood cells in the bone marrow resulting in an ‘overflow’ of immature white blood cells into the blood stream.
What causes CML?
Overactive intracellular cellular signalling pathways that lead to cell proliferation, growth and survival.
What causes the overactivation of cell signalling pathways in CML?
Expression of an oncogenic tyrosine kinase that is capable of phosphorylating, and hence activating, subsequent kinases in cell proliferation pathways including the Ras/MAPK pathway, PI3K/Akt pathway and the JAK/STAT pathway
What is Gleevec and what can it be used to treat?
Gleevec is a small molecule enzyme inhibitor given to patients with CML
How does Gleevec work?
Gleevec is capable of binding to BCR-ABL at the ATP binding site, preventing its phosphorylation. This in turn inhibits it from activating subsequent kinases in cell proliferation pathways
What are monoclonal antibodies?
A type of antibody used to treat some cancers that can inhibit cell surface receptors. These antibodies bind competitively with a receptors ligand binding site, preventing its activation via its ligand
What factors regulate enzyme activity?
Amount of enzyme Location of enzyme Amount of substrate Allosteric effectors Enzyme phosphorylation Regulatory proteins
What does the sequence at the N-terminus of a protein determine?
Stability of the protein; it indicates when the protein needs to be degraded
True or False:
Inducible enzymes are constantly required in the body
False
Constitutive enzymes are required constantly. Inducuble/repressible enzymes aren’t always needed
What enzymes are induced by insulin?
Hexokinase/glucokinase
PFK-1
Where is Glucose-6-phosphatase found?
Gluconeogenic tissues (liver and kidney)
True or False:
Isoenzymes are the result of different expression of a single gene
False
They are the product of different genes
Which isoenzyme has a higher affinity for glucose: Glucokinase or hexokinase?
Hexokinase (lower Km than glucokinase_
What state is PFK-2 in when it is phosphorylated?
Inactive
What state is FBPase-2 in when it is phosphorylated?
Active
When blood-glucose levels are low what hormone is secreted?
Glucagon
What feature of cells is stimulated by insulin?
GLUT 1-5 transporters
They facilitate the taking up of glucose by the cell
What regulates glucose hoeostasis?
Allosteric regulation of glycogen synthase and glycogen phosphorylase
Hormonal regulation
What do phosphatases do?
Remove phosphate groups
What do kinases do?
Add phosphate groups
What state is glycogen synthase when it is dephosphorylated?
Active
What state is glycogen phosphorylase when phosphorylated?
Active
What does the glucagon/epinephrine signalling pathway do?
Starts phosphorylation cascae via cAMP
Activates glycogen phosphorylase
What does glycogen phosphorylase do?
Cleaves glucose residues off glycogen, generating glucose-1-phosphate
What does the insulin-signalling pathway do?
Increases glucose import into muscle
Stimulates the activity of muscle hexokinase
Activates glycogen synthase
When do amino acids undergo oxidative phosphorylation?
Normal synthesis and degradation of cellular proteins
Diet rich in proteins
Starvation or uncontrolled diabetes mellitus
Where is glutamate dehydrogenase found?
In the liver