Biochemistry Flashcards
List the metabolic challenges to tumour cells
- Energy sources
- Protecting against oxidative stress
- Precursors for biosynthesis
Describe the Warburg effect and its role in cancer cell metabolism
- 18F-FDG is a glucose derivative that is radiolabelled and used as a tracer and taken up by glucose utilising cells
- Because of Warburg effect, tumour cells exhibit high capacity to take up 18F-FDG
- FDG cannot be further metabolised and accumulates in cells resulting in intense radiolabelling in cancer cells (inability of phosphofructo-kinase-1)
High capacity to take up FDG relates to the metabolic adaptation of cancer cells
Why do cancer cells exhibit enhanced glucose uptake?
Cancer cells over-express GLUT-1, a foetal form of glucose transformer
Why do cancer cells exhibit enhanced glycolytic flux?
Glycolytic enzymes hexokinase, PFK1 and lactase dehydrogenase (LDH) are over-expressed in cancer cells
Why do cancer cells exhibit diminished metabolic flux in TCA cycle?
Pyruvate dehydrogenase (PDH) activity is suppressed in cancer cells -> reduced rate of pyruvate metabolism
What usually occurs in hypoxia?
ROS/superoxide production occurs -? ROS damage of nuclear and mitochondrial DNA -? damaged DNA causes activation of tumour suppressor p53 -> p53 induces cell death, DNA repair, senescence and cell cycle arrest
How to cancer cells overcome/prevent hypoxia?
Glutathione (reduced) pairs with ROS and become oxidised -> reacts with NADPH to become reduced again (mopping up ROS)
How is NADPH produced in the context of cancer cells?
Through the pentose phosphate pathway
Explain the production of NADPH in the context of the PPP
hypoxia induces expression of glycogen synthase and glycogen phosphorylase -> hypoxic tumour cells store glycogen -> stored glycogen used to create glucose-6-phosphate -> creates NADPH for reducing glutathione
What does the Warburg effect have to do with the PPP and hypoxia?
Warburg effect is the over-expression of GLUT-1 allowing for the excess storage of glucose which then allows for this glucose to be used by PPP to create NADPH
What enzymes are involved with glycolysis?
Phosphoglucomutase and Hexokinase II
What enzymes are involved with glycogen metabolism?
Glycogen synthase 1, glycogen phosphorylase, glycogen branching enzyme 1
What enzyme is involved in the increased glucose uptake?
GLUT1 transporter
Hypoxia induces the activation of…
Hypoxia inducible factor (HIF-1)
Explain the role of glutamine metabolism in cancer cells
Increased expression of other enzymes to convert glutamine to form other amino acids like serine and glycine and also intermediates of TCA cycle like alpha-ketoglutarate to produce other precursors of biosynthesis of proteins and nucleic acids -> help with cancer cell proliferation
How to cancer cells undergo metabolic adaptations to maintain their high cell proliferation rate?
Non-oxidative phase of PPP -> generate precursors for DNA and protein synthesis
Explain the role of pyruvate kinase M2 in metabolic adaptation of cancer cells
- PKM2 has a lower activity than normal PK
- Cancer cells over-express pyruvate kinase M2 (PKM2) feeding the glycolysis cycle (going through to lactate rather than the TCA cycle)
Explain the role of pyruvate kinase M2 in metabolic adaptation of cancer cells
- PKM2 has a lower activity than normal PK
- Cancer cells over-express pyruvate kinase M2 (PKM2) feeding the glycolysis cycle (going through to lactate rather than the TCA cycle)
What are some ways metabolic liabilities can be exploited for cancer cell therapy?
- dietary restrictions to limit glucose availability
- inhibitors of glycogen phosphorylase
- inhibitors of hexokinase
- inhibitors/activators of PKM2
What is GLUT
glucose transporter
What is GLUT
glucose transporter
What are the kinases in glycolysis and what do they do?
hexokinase and glucokinase - turn glucose into phosphorylate glucose by using ATP trapping in the cell
Describe the rate limiting step in glycolysis
fructose 6 phosphate -> PFK1 -> fructose 1, 6-bisphosphate
What is the process that changes the rate of glycolysis when in a fed state
fed state -> insulin -> increased PFK2 -> fructose 2, 6-bisphosphate -> increased PFK1 = faster glycolysis
What is the process that changes the rate of glycolysis when in a fasting state
fasting state -> glucagon -> less PFK2 -> less fructose 2, 6 bisphosphate -> less PFK1 = slower glycolysis
In an anaerobic state what happens in glycolysis after fructose 1, 6-bisphosphate is made?
creation of ATP and converting until pyruvate kinase created pyruvate -> lactate dehydrogenase and NADH -> lactate + NAD+ (build up of lactate causes muscle soreness and NAD keeps glycolysis going)
In an aerobic state what happens in glycolysis after fructose 1, 6-bisphosphate is made?
creation of ATP and converting until pyruvate kinase created pyruvate -> moves to mitochondria -> krebs cycle = ATP
What is gluconeogenesis?
When in a prolonged fasting state gluconeogenesis allows the cells to make their own glucose for energy production, it is glycolysis in reverse with a couple of extra speedbumbs that requite the use of lactate, amino acids and glycerol
Describe the progression of type 2 diabetes
Type 2 diabetes is a progressive disorder - starts with insulin resistance. Can no longer bring about the effect of reducing blood sugar. Body pancreas initially secretes enough insulin to overcome glucose, no longer happens with type 2 diabetes. Insulin-resistant muscle with reduced glucose transport.
How does being overweight contribute to risk of diabetes?
Overweight = larger adipocytes
Pro-inflammatory state = enlarged adipocytes produce chemotaxis protein (MCP-1)
Chronic inflammation = macrophages infiltrate adipose tissue in response to MCP-1
Inhibit GLUT4, cannot access energy from glucose
Why is cholesterol important?
Steroid hormones are formed from cholesterol
Describe the steps used to synthesise thyroid hormones in the thyroid gland
Thyroglobulin -> thyroglobulin with iodinated Tyr residues -> Thyroxine (T4), Triiodothyronine (T3)
Describe the steps of alcohol metabolism
Ethanol –(Alcohol dehydrogenase)–> Acetaldehyde –(Aldehyde dehydrogenase) –> Acetate
