Metabolism Flashcards
Kinase
Catalyses phosphate transfer
Where does glycolysis occur
Cytoplasm
Preparative phase of glycolysis
Glucose
Glucose-6-phosphate
Fructose-6-phosphate
Fructose-1,6-bisphosphate
Dihydroxyacetone phosphate AND glyceraldehyde-3-phosphate
Preparative phase of glycolysis enzymes
Hexokinase
Phosphoglucoisomerase
Phosphofructokinase (PFK1)
Adolase
Isomerase
Rate limiting step of glycolysis
PFK-1
fructose-6-phosphate to fructose-1,6-bisphosphate
ATP generating phase of glycolysis
Glyceraldehyde-3-phosphate
1,3-bisphossphoglycerate
3-phosphoglycerate
2-phosphoglycerate
Phosphenol pyruvate
Pyruvate
OCCURS TWICE PER GLUCOSE MOLECULE
ATP generating phase of glycolysis enzymes
Triose phosphate dehydrogenase
Phosphoglycerate kinase
Phosphoglycerate mutase
Enolase
Pyruvate kinase
Anaerobic respiration
Pyruvate —> lactate
Anaerobic respiration enzyme
Lactate dehydrogenase
Purpose of anaerobic respiration
Regenerate NAD+ from NADH when no O2
What amplifies PFK1
AMP
Allosteric regulation of PFK-1
Fructose-2,6-bisphosphate
Citrate
ATP
Phosphoenol pyruvate
Inhibitor of pyruvate kinase
ATP
Amplifiers of pyruvate kinase
AMP
fructose-1,6-bisphosphate
Where does the link reaction occur
Mitochondrial matrix
Link reaction
Pyruvate —> acetyl CoA
Link reaction enzyme
Pyruvate dehydrogenase
Inhibitors of pyruvate dehydrogenase
Acetyl-CoA
ATP
Amplifier of pyruvate dehydrogenase
AMP
What is produced during link reaction
NADH + H+ + CO2
Ketogenesis in the liver
2 acetyl-CoA
Acetoacetyl-CoA
HMG-CoA
Acetoacetate
Beta-hydroxybutyrate and acetone
Enzyme converts acetyl-CoA to acetoacetyl-CoA
Ketones produced by ketogenesis
Acetoacetate
Acetone
Beta-hydroxybutyrate
What does 1 pyruvate molecule produce
3 NADH
1 FADH2
2 CO2
1 GTP
What is the kreb’s cycle inhibited by
NADH
ATP
What is the kreb’s cycle stimulated by
ADP
Where does the kreb’s cycle occur
Mitochondrial matrix
Kreb’s cycle
Acetyl-CoA
Citrate
Isocitrate
Alpha-ketoglutarate
Succinylcholine-CoA
Succinct
Fumarate
Maleate
Oxaloacetate
Rate limiting enzyme of kreb’s cycle
Isocitrate dehydrogenase
Enzymes of the kreb’s cycle
Citrate synthase
Aconitase
Isocitrate dehydrogenase
Alpha-ketoglutarate dehydrogenase
Succinyl-CoA synthase
Succinct dehydrogenase
Fumarate hydratase (fumarase)
Maleate dehydrogenase
Number of ATP produced per glucose molecule
38 ATP
Number of ATP produced per pyruvate molecule
19
ATP produced by glycolysis
2 ATP directly (4 ATP made and 2 ATP used)
6 ATP produced by 2NADH2 (3 each)
ATP produced by Kreb’s cycle per pyruvate
9 ATP produced by 3 NADH2 (3 each)
2 ATP produced by FADH2 (2 each)
Number of ATP produced by NADH2
3
Number of ATP produced by FADH2
2
Metabolism
Sum of chemical reactions that occur within each cell of an organism
Anabolic
Forming large molecules from small molecules, requires energy
Catabolic
Breaking down large molecules into smaller ones, creates energy
Kcal/g released by protein
4
Kcal/g released by carbohydrate
4
Kcal/g released by alcohol
7
Kcal/g released by lipid
9
Kcal/unit of alcohol
56
7 kcal/g x 8g (10ml=1unit) = 56 kcal/unit
Basal metabolic rate
Energy required to maintain non-exercise bodily functions (homeostasis)
Units of BMR
Kcal expended/hr/m^2
Henry equation
Estimates BMR based on age, weight and gender
Factors that increase BMR
Male (increased muscle mass)
Regular exercise
Caffeine
Young age (growing)
Temperature extreme
Disease
Hyperthyroidism
Pregnancy and lactation
Infection and chronic disease
Factors that decrease BMR
Starvation/ dieting
Old age (decreased muscle mass)
Hypothyroidism
BMI
Weight (kg)/ height (m^2)
When is O2 consumption measured to calculate BMR
When awake, rested and fasted for 12hrs
BMI normal weight range
18.5-25
BMI underweight range
0-18.5
BMI overweight range
25-30
BMI obese range
30-40
4 main pathways that dietary components are metabolised
• biosynthetic
• fuel storage
• oxidative processes
• waste disposal
Essential fatty acids
linoleic (omega 6) and alpha-linolenic (omega 3) series
Essential amino acids
lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, methionine, and histidine.
Which substrates are formed by the splitting of fructose-1,6-bisphosphate
Glyceraldehyde-3-phosphate
Dihydroxyacetone phosphate
Which enzyme catalyses the third reaction in the glycolysis pathway
Phosphofructokinase
Triacylglycerol
3 fatty acids esterified to one glycerol moiety (group)
Kcal requirement for an average hospital patient
25-35 kcal/day/kg
Dietary components
fuels, essential amino acids, essential fatty acids, vitamins, minerals, water, xerobiotics (foreign substances eg drugs)
Storage of excess fat
adipose tissue (only 15% water) as triglycerides (for 70kg man approx. 15kg)
Amount of fat stored in average 70kg man
15kg
Storage of excess carbohydrates
glycogen in liver (for 70kg man up to 200g) and muscles (70kg man- 150g)
Average amount of glycogen stored in liver for 70kg man
200g
Average amount of glycogen stored in muscles for 70kg man
150g
Storage of excess protein
muscle (80% water) (for 70kg man approx. 6kg)
Average amount of protein stored as muscle in 70kg man
6kg
What percentage of muscle is water
80%
What percentage of adipose tissue is water
15%
How many kJ is 1 Kcal
4.18 kJ
BMI severely obese range
40+
Rough estimate of BMR
1 kcal/kg body mass/hour
What is BMR proportional to
Amount of metabolically active tissue (including the major organs) and the lean (or fat free) body mass
How is BMR measured
CO2 produced
When does BMR apply
• post-absorptive (12 hour fast)
• lying still at physical and mental rest
• Thermo-neutral environment ( 27 -29°C)
• No tea/coffee/nicotine/alcohol in previous 12 hours
• no heavy physical activity in previous 24 hours
• establish steady state (30 mins)
Why is BMR generally higher in children
Greater proportion of metabolically active tissue
Why is BMR usually lower in women than men
More adipose tissue and less muscle mass
Resting metabolic rate
30% higher than basal metabolic weight for a very sedentary person and a value of 60% to 70% of the BMR (per day) for a person who engages in about 2 hours of moderate physical activity per day A value of 100% or more of the BMR is used for a person who does several hours of vigorous physical activity per day.
Malnutrition
a state of nutrition with a deficiency, excess or imbalance of energy, protein or other nutrients, causing measure adverse effects on tissue/body shape/size/composition, body function and clinical outcome
Starvation
• Overnight fast - decreases insulin secretion → glycogenolysis (break down glycogen to produce glucose)
Brain requires approx 150g glucose/day. After an overnight fast, liver has about 80g glycogen
• Longer fasts necessitate gluconeogenesis (uses lactate, amino acids (muscle, intestine, skin breakdown) and glycerol (fat breakdown))- decrease insulin secretion and increased cortisol secretion - lipolysis and proteolysis
• >4 days- liver creates ketones from fatty acids, brain adapts to using ketones (ketones are acidic so excess causes blood pH to fall- ketoacidosis- prevent enzyme function), BMR falls (accommodation)
DEE
Daily energy expenditure
What does complete oxidation of proteins produce
CO2, H2O, NH4+
Why does lipid oxidation produce the most energy
more reduced so can oxidise more to produce more energy
Name of vitamin A
Retinol
Name of vitamin D
Calciferol
Name of vitamin E
Tocopherol
Name of vitamin K
Phylloquinone, Menaphthone
Name of vitamin C
Ascorbic acid
Name of vitamin B12
Cobalamin
Name of vitamin B1
Thiamin
Name of vitamin B2
Riboflavin
Name of vitamin B3
Niacin
B vitamins
B1, B2, B3, pantothenic acid, B6, biotin, folate, B12
Vitamin C
ascorbic acid, fruit and vegetables, heat labile, collagen synthesis, improve iron absorption, antioxidant
Destroyed by heat
Lack of vitamin C = Scurvy
Vitamin B12
cobalamin, protein synthesis, DNA synthesis, regenerate folate, fatty acid synthesis, energy production
Broken down in stomach with cofactor
Absorbed in terminal ileum
How long does carbohydrate provide energy for
glycogen to sustain energy levels for 12 hours
How long does fats provide energy for
provide energy for up to 12 weeks
When is protein used as an energy source
used when muscle glycogen stores fail
The prudent diet
• 5+ servings of fruit/vegetables
• Base meals around starchy (complex) carbohydrates
• No more than 5% energy should come from free sugars (glucose, fructose)
• 0.8 g/kg/day protein
• Saturated fat: no more than 30g/day for men & 20g/day for women
• No more than 2.4g/day of sodium (6g salt)
• No more than 14 units alcohol / week (over at least 3 days)
• Adequate calcium
How much protein should we consume according to the prudent diet
0.8g/kg/day
How much sodium should we consume according to the prudent diet
2.4 g/day (6g salt)
How much saturated fat should we consume according to the prudent diet
No more than 30g per day for men
No more than 20g per day for women
How much energy should come from free sugars (glucose, fructose) according to the prudent diet
No more than 5%
Major minerals required in the diet
Sodium
Potassium
Calcium
Chloride
Phosphorus
Magnesium
Kinase enzymes
Moves phosphate group
ATP
currency of metabolic energy- a high energy molecule composed of adenine, ribose and 3 phosphate groups
Hydrolysis of ATP to ADP and Pi
energy is stored in phosphate bonds
Need for glycolysis
• emergency energy producing pathway when oxygen is limiting (erythrocytes and exercising skeletal muscle)
• Generates precursors for biosynthesis:
• Glucose-6-Phosphate converted to ribose-5-P (nucleotides) via pentose phosphate pathway and G-1-P for glycogen synthesis
• Pyruvate- transaminated to alanine, substrate for fatty acid synthesis
• Glycerol-3-P is backbone of triglycerides
Which enzyme phosphorylates glucose to glucose-6-phosphate
Hexokinase using ATP
Which enzyme isomerises glucose-6-phosphate to fructose-6-phosphate
Phosphoglucose isomerase
Which enzyme phosphorylates fructose-6-phosphate to form fructose-1,6-bisphosphate
Phosphofructokinase-1 using ATP
Which enzymes cleaves fructose-1,6-bisphosphate to form glyceraldehyde-3-phosphate and dihydroxyacetone phosphate
Adolase
Which enzyme isomerises dihydroxyacetone phosphate to glyceraldehyde-3-phosphate
Triose phosphate isomerase
Which enzyme oxidises glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate
Triose phosphate dehydrogenase
What is produced when Triose phosphate dehydrogenase oxidises glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate
2 molecules of NADH
Which steps of glycolysis require ATP
Glucose —> glucose-6-phosphate
Fructose-6-phosphate —> fructose-1,6-bisphosphate
Which enzyme converts 1,3-bisphosphoglycerate to 3-phosphoglycerate
Phosphoglycerokinase
Which enzymes isomerises 3-phosphoglycerate to form 2-phosphoglycerate
Phosphoglyceromutase
Which enzyme isomerises and dehydrates 2-phosphoglycerate to form phosphoenolpyruvate
Enolase
Which enzyme produces pyruvate from phosphoenolpyruvate
Pyruvate kinase
Which 2 stages of glycolysis produce 2 ATP molecules by substrate-level phosphorylation
1,3-bisphosphoglycerate —> 3-phosphoglycerate
Phosphoenolpyruvate—> Pyruvate
How is ATP produced during glycolysis
Substrate level phosphorylation
Which are irreversible phases of glycolysis
Glucose —>glucose-6-phosphate
Fructose-6-phosphate —>fructose-1,6-bisphosphate
Phosphoenolpyruvate—> pyruvate
Allosteric regulation of glycolysis
molecule binds to a non-catalytic site, conformational change which changes affinity for the substrate
What does ATP inhibit in glycolysis
PFK1
(Reduces energy wastage)
What does AMP activate in glycolysis
activator of PFK1, when ATP is used up, ADP accumulates and is converted to AMP by adenylate kinase reaction to generate ATP 2ADP = ATP + AMP
What does citrate inhibit in glycolysis
inhibits PFK1 so a signal cycle does not need more fuel
What does fructose-2,6-bisphosphate inhibit in glycolysis
generates from fructose-6-phosphate, inhibitor of PFK1, mediates
effect of insulin and glucagon
How does acidosis affect glycolysis
Inhibits PFK1
Hormonal regulation of glycolysis
insulin and glucagon. Indirect route through affecting regulatory molecules (eg kinases or phosphatases)
Increases or decreases gene expression for the enzyme
Increase or decrease enzyme activity
Fate of pyruvate- anaerobic conditions
lactate formation catalysed by lactate dehydrogenase. Regeneration of NAD+ by oxidation
Important to allow glycolysis to continue so it can produce one ATP in low O2 conditions or erythrocytes
Glucose + 2ADP + 2Pi → 2 lactate + 2 ATP + 2H2O + 2H+
Cori cycle
prevent build up of lactic acid and muscle fatigue
Gluconeogenesis of lactate
In liver, gluconeogenesis of lactate to glucose through lactate dehydrogenase
In hepatocytes
Fate of pyruvate - aerobic conditions
enters mictochondria and converted to Acetyl CoA and CO2 by pyruvate dehydrogenase in a decarboxylation reaction (link reaction). Acetyl CoA can enter Kreb’s cycle for more energy production .
Inhibited allosterically by its products Acetyl CoA, ATP and NADH when in high concentrations, and products indirectly act by activating a kinase that phosphorylates and inhibits PDH
Decarboxylation of pyruvate to Acetyl-CoA is irreversible
Pyruvate + CoA + NAD+ → Acetyl-CoA + CO2 + NADH + H+
Which enzyme converts pyruvate to Acetyl CoA
Pyruvate dehydrogenase
Inhibition of link reaction
allosterically by its products Acetyl CoA, ATP and NADH when in high concentrations, and products indirectly act by activating a kinase that phosphorylates and inhibits PDH
Fast glycolytic fibres
Sparse capillaries
Sparse mitochondria
Sparse myoglobin
Low oxidative capacity/ high glycolytic
Easily fatigued
High ATPase activity
Fast contractions
Slow oxidative fibres
Abundant capillaries
Abundant mitochondria
Abundant myoglobin
High oxidative capacity
Fatigue resistant
Low ATPase activity
Slow contractions
Reason for Kreb’s cycle
• Generates lots of energy in form of ATP
• provides final common pathway for oxidation of carbohydrates, fat and protein via Acetyl CoA
• produces intermediates for the synthesis of amino acids, glucose, heme etc
• Sequence of 8 enzymatic reactions
• Acetyl CoA condenses oxaloacetate forming citrate
• Oxaloacetate is regenerated in the last step of the krebs’ cycle and 2 CO2 molecules released
• Energy is harvested in the form of NADH, 2FADH2 and ATP molecules
Pneumonic for kreb’s cycle order
Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate
Which enzyme combines acetyl CoA and oxaloacetate to form citrate
Citrate synthase
Which enzyme isomerises citrate to isocitrate
Aconitase
Which enzyme oxidises and dehydrogenates isocitrate to form alpha-ketoglutarate
Isocitrate dehydrogenase
What is produced when alpha-ketoglutarate is formed
CO2 and NADH
Which enzyme converts alpha-ketoglutarate to succinyl-CoA
Alpha-ketoglutarate dehydrogenase
What is produced when succinyl-CoA is formed
CO2 and NADH
Which enzyme converts succinyl-CoA to succinate
Succinate thiokinase
What is produced when succinate is formed
Phosphorylation of GDP to GTP which is then converted to ATP
Which enzyme oxidises succinate to form fumarate
Succinate dehydrogenase
What is produced when fumarate is formed
FADH2
Which enzyme converts fumarate to malate
Fumarate hydrase (by addition of water)
Which enzyme converts malate to oxaloacetate
Malate dehydrogenase
What is produced when oxaloacetate forms
NADH
Regulation of kreb’s cycle
• rate determined by levels of ATP, NADH, FADH2- high levels inhibit Krebs’ cycle
• Activated by high ADP
• Alpha-ketoglutarate dehydrogenase as activated by Ca2+ (muscle contraction)
• if cycle inhibited, build up of Acetyl CoA so undergoes fatty acid synthesis
What inhibits pyruvate dehydrogenase
ATP, NADH, Acetyl-CoA
What activates pyruvate dehydrogenase
ADP
What inhibits citrate synthase
ATP, NADH, citrate
What activates citrate synthase
ADP
What inhibits isocitrate dehydrogenase
ATP, NADH
What activates isocitrate dehydrogenase
ADP
What inhibits alpha-ketoglutarate dehydrogenase
ATP, NADH, GTP, succinyl-CoA
What activates alpha-ketoglutarate dehydrogenase
Ca2+
Where does oxidative phosphorylation occur
occurs in inner mitochondrial membrane, aerobic conditions
Oxidative phosphorylation
- Components of ETC accept electrons (reduced) and pass them on (oxidised).
- Electrons are transferred to final electron acceptor O2 (which is reduced by hydrogen to form water)
- Free energy drop as electrons are passed down ETC
- Free energy is used to pump H+ across the inner membrane space via the Cytochrome-C oxidase complex, creating a proton motive gradient
- ATP synthase contains a proton pore
- ATP produced as protons flux in through ATP synthase- energy coupled to chemiosmosis (about 28 ATP molecules)
- In the matrix, the H+, electrons and oxygen combine to form water as O2 is the final electron acceptor
1/2O2 + 2e- + 2H+ → H2O
Complex I
Removes electrons from NADH
Complex II
Removes electrons from FADH2 in prescence of coenzyme Q (ubiquinone)
Complex III,IV and cytochrome C
donate electrons to cytochromes containing iron (anemia and OXPHOS diseases decreases mitochondrial capacity for oxidative phosphorylation)
Why must protons move via ATP synthase
Inner mitochondrial membrane is impermeable
What causes an increased metabolic rate and heat generation - oxidative phosphorylation
Proton leakage, chemical uncouplers and regular uncoupling protons
What is rate of ETC coupled with
rate of ATP synthesis by the transmembrane electrochemical gradient As ATP is used for energy-requiring processes and ADP levels increase, proton influx through the ATP synthase pore generates more ATP, and the electron transport chain responds to restore Δp. In uncoupling, protons return to the matrix by a mechanism that bypasses the ATP synthase pore, and the energy is released as heat.
Steady energy state of cell
balance ATP generation
Maintenance of stable blood glucose
• Low glucose is damaging to cells/brain
• High glucose is damaging (glycosylation of proteins)
• Maintained through action of anabolic hormones (insulin) and catabolic hormones (glucagon, catecholamines)
Normal blood glucose range
4.5-5.5 mmol/L
Main ketones in body produced by citric acid cycle from Acetyl CoA
Acetone
Acetoacetone
Beta-hydroxybutyrate
Synthesis of ketones
• occurs when high ATP levels which inhibits the Krebs’ cycle and was to a build up Acetyl CoA
• Occurs in cytosol of cell
• But Acetyl CoA cannot cross mitochondrial membrane
Fatty acids
• carboxylic head group with aliphatic tail
• Long acyl CoA chains
• saturated and unsaturated
• most are derived from triglycerides and phospholipids
18 carbon fatty acid
Linoleic acid
Oleic acid
16 carbon fatty acid
Palmitic acid
20 carbon fatty acid
Arachidonic acid
Lipid absorption
- Bile salts emulsify dietary fats in small intestine, forming mixed micelles
- Intestinal lipases degrade triacylglycerols
- Fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into triacylglycerols
- Triacylglycerols are incorporated with cholesterol and apoproteins into chylomicrons
- Chylomicrons move through the lymphatic system and bloodstream to tissues
- Lipoprotein lipase, activated by apoC-II in the capillary, releases fatty acids and glycerol
- Fatty acids enter cell
- Oxidised as fuel or reesterified for storage
What is lipoprotein lipase activated by
apoC-II in the capillary
What forms chylomicrons
Triacylglyerols
Cholesterol
Apoproteins
Fatty acid activation
• must be activated in the cytoplasm before they can be oxidised in the mitochondria
• if the acyl-CoA has < 12 carbons - can diffuse through mitochondrial membrane
• most dietary fatty acids have > 14 carbons - taken through mitochondrial membrane using the carnitine shuttle
Fatty acid → acyl adenylate → acyl CoA
ATP -> PPi. HS-CoA -> AMP
Fatty acid activation equation
Fatty acid → acyl adenylate → acyl CoA
What enzyme converts acyl adenylate to acyl-CoA
Acyl-CoA synthase
Citrate shuffle
• oxaloacetate bonds with Acetyl CoA to produce citrate- can cross mitochondrial membrane into cytosol
• Citrate ligase converts citrate back to oxaloacetate which is then broken down into pyruvate and Acetyl CoA
• Pyruvate recycled back into mitochondria and converted to oxaloacetate so can re-enter Krebs’ cycle
• Acetyl-CoA converted into fatty acids
Carnitine shuffle
• the acyl-CoA chains are converted and reformed in order to cross the membrane
• Acyl-CoA to acyl carnitine by carnitine acyltransferase 1 (CAT1)- Located on outer mitochondrial membrane
• CoA is recycled
• acyl carnitine is reformed to acyl CoA by cartinine acyltransferase 2 (CAT2)- On interior of membrane
• Cartinine recycled through the outer membrane
Fatty acid beta-oxidation
Energy derived from fatty acid beta-oxidation
• once acyl-CoA has crossed the membrane it can now be oxidised
• This involves the sequential removal of 2 carbon units by oxidation- the second (hence beta) carbon is cleaves
• Each round produces 1 NADH, 1 FADH2, and 1 Acetyl-CoA
• FADH2 and NAD undergo oxidative phosphorylation
• Acetyl-CoA re-enters the krebs’ cycle
• ATP is produced
• Oxidation →hydration →oxidation →thiolysis
When does fatty acid beta-oxidation occur
Occurs in response to decreased blood glucose and high glucagon
Fatty acid beta-oxidation molecules
Acyl-CoA —> Acetyl-CoA
Following oxidation -> hydration-> oxidation ->thiolysis
Which enzyme is involved in first oxidation in fatty acid beta-oxidation
Acyl-CoA dehydrogenase
Which enzyme is involved in hydration in fatty acid beta-oxidation
Enol-CoA hydrase
Which enzyme is involved in second oxidation in fatty acid beta-oxidation
Hydroxyacyl CoA- dehydrogenase
Which enzyme is involved in thiolysis in fatty acid beta-oxidation
Thiolase
What does each round of fatty acid beta-oxidation produce
1 NADH
1 FADH2
1 Acetyl-CoA
Utilisation of acetyl-CoA
• under normal metabolic conditions most Acetyl-CoA is utilised via the TCA acid cycle to produce glucose
• A small proportion is converted to ketones
• Ketones- molecules produced by the liver from Acetyl-CoA - have a characteristic fruity/nail polish remover-like smell
• during high rates of fatty acid oxidation, large amounts of Acetyl-CoA are generated
• this exceeds the capacity of the krebs’ cycle, which results in ketogenesis
Ketones
molecules produced by the liver from Acetyl-CoA - have a characteristic fruity (pear drops)/nail polish remover-like smell
Causes of respiratory alkalosis
hyperventilation in response to hypoxia
Causes of metabolic acidosis
renal failure, loss of HCO3-, excess H+ production
Respiratory acidosis
PaCO2 increases leading to an increase in H+ ions and so pH decreases
• CO2 production is greater than CO2 elimination
Ketogenesis
• acetoacetate can undergo spontaneous decorboxylation to acetone, or be enzymatically converted to beta-hydroxybutyrate
• ketone bodies utilised by extrahepatic tissues through conversion of beta-hydroxybutyrate and acetoacetate to acetoacetyl-CoA
• this requires the enzyme acetoacetate: succinyl-CoA transferase, which is found in all but hepatic tissue
• When glycogen levels in liver are high, beta-hydroxybutyrate production increases
Ketogenesis reactions
2 acetyl-CoA —> acetoacetyl CoA—> 3-hydroxy-3-methyl glutaryl CoA (HMG CoA)—> acetoacetate —> EITHER alpha-beta-hydroxybutyrate OR acetone
Which enzyme converts 2 acetyl CoA to acetoacetyl CoA
Thiolase
Which enzyme converts acetoacetyl CoA to 3-hydroxy-3-methyl glutaryl CoA
HMG CoA synthase
Which enzyme converts 3-hydroxy-3-methyl glutaryl CoA to acetoacetone
HMG CoA lysase
Which enzyme converts acetoacetone to alpha-beta-hydroxybutyrate.
Alpha-beta-hydroxybutyrate dehydrogenase
Which enzyme converts acetoacetate to acetone
NONE
it occurs spontaneously
Regulation of ketogenesis affected by
• release of free fatty acids from adipose tissue- more fatty acids, more ketones
• a high concentration of glycerol-3-phosphate in the liver results in triglyceride production, whilst a low level results in increased ketone body production
• when demand for ATP is high, Acetyl-CoA is likely to be further oxidised via the TCA cycle to CO2
• fat oxidation is dependent upon the amount of glucagon (activation) or insulin (inhibition) present
Clinical significance of ketogenesis
• during normal physiological conditions the production of ketones occurs at a low rate
• carbohydrate shortages cause the liver to increase ketone the body production from Acetyl-CoA
• the heart and skeletal muscles preferentially utilise ketone bodies for energy preserving glucose for the brain
Ketoacidiosis
• occurs in insulin-dependent diabetics when dose is inadequate or because of increased insulin requirement (infection, trauma, acute illness)
• often the presenting feature in newly diagnosed type 1 diabetics
• also occurs in chronic alcohol abuse and starvation
• patients present with hyperventilation and vomiting
Consequences of ketoacidosis
ketones are relatively strong acids (pKa~ 3.5). Excessive ketones lower blood pH which impairs ability of haemoglobin to bind to oxygen
Blood test ketoacidosis
pH- low
pO2- high
pCO2- low
HCO3- low
CO2 low as acidic so hyperventilate to remove CO2 from blood to compensate for acidic ketones and lots of O2
HCO3 bicarbonate (base) trying to neutralise blood so low levels left
Diabetic ketoacidosis
Insulin deficiency:
1. Inhibition of glycolysis and stimulation of glyconeogenesis
2. Glycogen breakdown and inhibition of glycogen synthesis
3. Increased lipolysis (increased free fatty acids)
-1 and 2 lead to hyperglycaemia
-3 leads to Increased acetoacetate and beta-hydroxybutyrate (Can be oxidised as fuels in most tissues (eg skeletal muscle))
Treatment of diabetic ketoacidosis
• sliding scale of insulin
• IV fluid hydration (10% dextrose and 0.9% saline)
• monitor fluid balance closely
• 40 mmol potassium
• pabrinex: injection containing vitamins C, B1, B2, B3, B6
Alcoholic ketoacidosis
High blood EtOH concentration
Depleted protein and carbohydrate stores:
1. Impaired gluconeogenesis
2. Decreased insulin and increased glucagon secretion
Increased lipolysis (increased free fatty acids)
Increased ketone production
3 biological buffers
Protein
Haemoglobin
Bicarbonate
Homeostasis
Maintenance of a stable internal environment eg temperature, glucose, potassium, blood oxygen, hydrogen ions
Normal pH range of body
7.35-7.45
Endocrine glands
Ductless
Release hormones into blood
Auto rinse
messenger molecules bind with receptors in cell where they are produced eg chemical/secondary messengers
Paracrine
messengers in ECF eg clotting factors, prostaglandins in childbirth, inflammatory mediators, interleukins signalling in immune system mainly between white blood cells, platelet derived growth factor releases from platelets and regulates cell growth. Signal diffuses across gap between cells. Inactivated locally so doesn’t enter blood stream
Endocrine
secretions into blood eg insulin
Exocrine
secrete substances through ducts onto your body surfaces. Exocrine glands secrete sweat, tears, saliva, milk and digestive juices
Endocrine organs and glands
hypothalamus, pituitary, thyroid, adrenals, pancreas, ovaries, testes, skin, heart
Peptide hormones
Made of short amino acid chains (some have carbohydrate side chains- glycoproteins)
Hydrophilic so can dissolve in blood
Stored in cell and released when needed/signalled
Binds to a receptor on membrane
Produces a quick response via a secondary messenger cascade (eg cAMP, Ca2+)
Eg insulin, growth hormone, TSH and ADH
Amino acid derivatives hormones
Synthesised from tyrosine
Acts in same way as peptide hormones
Eg adrenaline (epinephrine), thyroid hormones (T4 and T3)
What are all amino acid derivatives synthesised from
Tyrosine
Steroid hormones
Synthesised from cholesterol
Water insoluble and lipid soluble- can cross membranes but requires transport proteins in blood
Intercellular receptor target
Synthesised on demand
Steroid hormone made in cell and diffuses out once made (not stored)
Directly affects DNA and alters transcription/translation- slow response as proteins have to be made
Eg testosterones, oestrogen, cortisol
Example of steroid hormone transport proteins
Albumin
Sex hormone binding globulin
What are all steroid hormones synthesised from
Cholesterol
Positive feedback loop
signal is amplified
• when a deviation from an optimum causes changes that results in an even greater deviation from the normal e.g. During birth oxytocin released due to increased pressure, which causes more contractions, increasing pressure, releasing more oxytocin; action potentials; bone repair (osteocalcin) or hypothermia/hyperthermia
Negative feedback loop
when the change produced by the control system leads to a change in the stimulus detected by the receptor and turns the system off (system is restored to its original level)
• eg blood glucose
When is beta oxidation used
Beta oxidation is used in aerobic conditions as fuel when there is increased demand
e.g. during fasting or states of low blood glucose. However it cannot be used as fuel for the nervous system because fatty acids cannot pass the blood-brain barrier
