22. Extremes of Metabolism Flashcards
Describe the 2 types of muscle fibre.
What changes the proportions of these fibres?
Type I slow twitch: develop tension slowly using oxidative metabolism from glucose and in the longer term fatty acids. Mitochondria rich
Type II fast twitch: uses anaerobic metabolism generating ATP via glycolysis -> lactate. Main fuel = glycogen, switching to blood glucose during longer periods of exercise. Affected by McArdles (Glycogen storage disease type V). Subtypes: A - contain mitochondria and myoglobin thus also aerobic (although first burst of energy from glycolysis), B - anaerobic, few mitochondria, dependant on glycolysis and cori cycle
Type of exercise/training done. Genetic component too.
List the sources that can regenerate ATP to meet muscle metabolic demand during exercise. (In order of what is used first)
How do levels of AMP influence metabolism?
Does muscle glycogen have sufficient capacity to provide ATP during sprinting?
1) Phosphocreatine (15kJ stored) (quick)
2) Muscle glycogen (8000 kJ stored) (quick, for short intense bursts)
3) Blood glucose/ blood FAs (triacylglycerol) (17500 kJ stored) (slower)
Important metabolic signal, if levels rise = increases glucose uptake/utilisation in the short term and fatty acid oxidation in the long term
Yes
How is ATP breakdown linked to muscle contraction during exercise?
How is PDC controlled?
Ca2+ activates phosphorlyase kinase a via Ca2+ binding subunit (calmodulin). This phosphorylates glycogen phosphorylase, which breaks down glycogen. Thus increased Ca2+ is linked to muscle contraction. Ca2+ also acts as allosteric effector of glycolysis and speeds it up.
(Controls entry to TCA) Phosphorylation via PD kinase, which responds to ATP and NADH levels. The phosphatase responds to Ca<strong>2+</strong> (activates it, thus activating PDC). PDC is also alosterically activated by low NADH and ATP concentrations = keep PDC active.
Apart from PDC, what other 2 enzymes are also controlled allosterically by calcium?
Levels of what other substance also affects the same 3 enzymes as calcium?
What other substance also stimulates the two ETC enzymes the one in question 1 does?
What 2 ways does AMP influence metabolism?
Isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase. Thus when muscle contracts = activates energy metabolism!
NADH - if levels are low, drives reactions forward to replenish NADH.
ADP: drives the reactions when low
1) allosterically activates enzymes at start of glycolysis (PFK1-) and glycogenolysis (glycogen phosphorylase)
2) increases number of GLUT4 plasma membrane channels
How does AMP act as an allosteric activator of glycogen phosphorylase?
What allosterically inhibits PFK-1, and what is this relieved by?
What PFK-2 mechanism occurs in the heart?
Only does this when it’s phosphorylated (i.e. can make the usually inactive form active by inducing similar enzymatic properties as the phosphorylated enzyme), thus promoting glucose breakdown.
High levels of ATP. Relieved by ADP/AMP.
PFK-2 (when phosphorylated by AMP kinase) produces fructose-2,6-bisphosphate which allosterically activates PFK-1. Also when AMP levels high -> increases flow through glycolysis = direct
Describe AMP kinase.
Apart from AMP binding, what else does AMP kinase do?
What happens to metabolism during prolonged exercise, and how is AMP kinase involved?
Heterotrimer of 3 subunits: 2 regulatory and 1 catalytic. It senses energy status (cellular AMP) via specific domains on gamma subunit -> phosphorylates PFK-2. It can also be controlled by phosphorylation on Thr172 of the alpha subunit (not AMP dependant, but don’t worry too much about this)
Promote movement of GLUT4 to membrane (insulin - INdependant)
Shift from glucose to fatty acid metabolism. Mediated by AMP kinase which phosphorylates cytoplasmic acetyl-CoA carboxylase, preventing build up of this in the cytoplasm. (Normally active ACoAC converts ACoA to malonyl CoA whcich inhibits fat transport into mitochondria - the carnitine shuffle). This activates the carnitine shuffle transporting fatty acids into mitochondira for breakdown (beta oxidation). Thus when AMP is high -> SWITCH ON FAT BURNING
Describe 4 things that cause muscle fatigue during exercise.
1) Running out of glycogen: marathon runner needs 700g glycogen but there is only 500g in body. Multiple-sprint sports - muscle glycogen is depleted according to duration of burst relative to rest. Longer term fatty acid oxidation allows a power output of only 60% max (i.e supplies less ACoA)
2) Depletion of phosphocreatine: reduce ability to regenerate ATP -> fatigue more easily (so max out glycogen and PCr before race = fatigue later)
3) Excessive rates of converstion of glycogen -> lactic acid. Decreases pH and inhibits glycolysis and oxidative phosphorylation: if intense exercise.
4) Insufficient (aging - less mit), inflexible (obesity), or inefficient mitochondria. Mit density increases with exercise - longer distances = more mit!
As the body progresses through starvation, what energy sources are used?
During prolonged starvation, the different tissues produce things for each other to use. Give some examples.
Glucose -> glycogen -> GNG -> GNG and ketogenesis
Break down fat in adipose tissue (lipolysis) -> FA to liver to make ketone bodies for the brain, kidneys and muscle. FA also stored by muscle as an alturnative form to glucose (mostly slow-twitch). Liver takes glycerol, lactate and AA for gluconeogenesis to make glucose -> send to brain and cells that can’t metabolise e.g. RBC.
What are the 3 pathways for alcohol metabolism?
1) Alcohol dehydrogenase catalyses: Ethanol + NAD+ -> acetaldehyde + NADH + H+ in liver. Variation in populations e.g. alcohol dehydrogenase gene less active in some races = don’t break ethanol down as quick.
2) Catalase: produces water
3) Microsomal ethanol oxidising system [P450]: produces NADP and water
What happens to the toxic acetylaldehyde from ethanol breakdown?
What is the role of disulfiram?
What are the biochemical effects of alcohol?
1) Acetyladehyde + NAD+ -> acetate + NADH, catalysed by acetylaldehyde dehydrogenase
2) Acetate then conjugated to CoA: ATP + acetate + CoA -> AMP + PPi + ACoA
Antabuse: inhibits acetylaldehyde dehydrogenase so get all unpleasant effects of alcohol - discourages alcoholics from drinking
Produces lots NADH: inhibits TCA (inhibits malate dehydrogenase), drives lactate dehydrogenase to producing lactate (away from pyruvate), blocks PDC (blocks glycolysis and TCA). Also inhibits malate dehydrogenase so blocks GNG too.
Produce lots ACoA: TCA disrupted so they’re shunted to FA biosynthesis and ketone body production, so produce more lactate and ketone bodies = potenitally acidfying blood! NB: like starvation (fat synth and KB!)
They immune system has variable energy demand. Describe 3 things that it does that require energy.
How can the TCA in the immune cell be used for generation of other substances?
1) ROS: high flow through pentose phosphate pathway produces NADPH, which produces ROS to attack bacteria. Can also produce NADPH in cytoplasm from malate to feed into this (so immune cells dependant on AA glutamine to produce lots of malate to produce ROS)
2) Anabolism of immune mediators e.g. immunoglobins
3) Phagocytosis
Take intermediates from TCA for biosythesis. Ok b/c glutamine/glutamate can form alpha-ketoglutarate to top up TCA cycle to keep it going. Malate withdrawn to make ROS.
Why do cancer cells produce lots of lactate EVEN in the presence of oxygen?
What can cancer cells do that is similar to immune cells?
Explain cancer cell heterogeneity.
How do the new cancer drugs differ from the old ones target-wise? Will this not also affect normal cells?
Warburg effect: cancer cells have a high energy demand b/c growing all the time and produce more pyruvate than can be fed into TCA, so predominantly produce energy by a high rate of glycolusis. HIF1 gene drives up glycolysis increasing Warburg effect.
Cancer cells can also use glutamine and glutamate as fuel (like immune cells BUT they use for energy rather than topup).
Diff cells in tumour doing different things e.g. diff metabolism and provide diff metabolites for each other. (Cori cycle happens in cancer cells! Related to amount of O2, so if further from capillary do glycolysis, and if closer regenerate lactate -> glucose. Allows survival of whole tumour).
Now target metabolism rather than cell growth/proliferation e.g. interact with hexokinase, pyruvate kinase, glucose transport, glutamine uptake etc. Will affect normal cells but cancer cells MORE b/c they’re so much more dependant on energy
