Metabolism 2 Flashcards
Give 2 methods of synthesising acetyl coA
glycolysis + link reaction
Fatty acid oxidation
What can acetyl coA be used for
sterols and fatty acids
TCA
ketone bodies
protein acetylation
Compare unsaturated to saturated fatty acids
both are hydrocarbon chains with -COOH at the end
unsaturated= 1 or more double bonds, liquids e.g. plant oils
saturated= no double bonds, solids e.g. animal fat
What is the structure of a triglyceride
1 glycerol and 3 fatty acids bonded together by ester bonds
How are fatty acids stored
stored as triglycerides in adipocytes
compare the caloric yield of fat to glucose
38 ATP vs 129 ATP
How much of energy is from fat in the human body
50%, except for in the brain where only glucose and ketone bodies are used
What can fatty acids be involved in metabolically
conversion to acyl coA
transport to the mitochondrial matrix
bet oxidation
acetyl coA production
What is acyl coA used for and how is it synthesised
used for beta oxidation
outer mitochondrial membrane
acyl coA synthetase converts the fatty acid to any cop while ATP is converted to AMP (2 high energy bonds broken)
How is acyl coA transported to the mitochondria
carnitine shuttle
carnitine is converted to acyl carnitine via acyl coA by carnitine acyltransferase I
acyl carnitine transported into the matrix via translocase
acyl carnitine converted to carnitine via coA
What are the 4 main reactions of beta oxidation
oxidation
hydration
oxidation
thiolysis
Explain the process of beta oxidation
- Acyl coA is oxidised by FAD via Acyl coA dehydrogenase
- 3-hydroxyacyl hydrolase hydrates the product
- oxidation of the product via L-3-hydroxyacyl coA dehydrogenase
- Splitting of the product into acyl CoA -2C + Acetyl coA by beta-ketothiolase
this repeats until the fatty acid is broken down (no. of cycles = /2,-1)
When can acetyl coA enter the TCA cycle
beta oxidation and carb metabolism is balanced (oxaloacetate needed for entry)
What occurs when fat metabolism > carb metabolism and when may this occur
occurs during fasting
acetyl coA forms acetoacetate, D-3 hydrocybutyrate and acetone (ketone bodies)
Explain how ketone bodies are formed from acetyl coA
- acetyl coA -> acetoacetyl coA
- acetoacetyl coA -> 3-hydroxy-3-methyl glutaryl coA
- 3-hydroxy-3-methyl glutaryl coA -> acetoacetate
- acetoacetate -> D-3 hydroxy butyrate + acetone
What are the 4 main reactions of fatty acid synthesis
decarboxylative condensation
reduction
dehydration
reduction
Explain the process of decarboxylative condensation in fatty acid synthesis
Aims to make a donator malonyl coA (3C)
- acetyl coA is converted to malonyl coA by acetyl coA carboxylase, using ATP
- malonyl coA binds to ACP (acyl carrier protein) which swings from one domain to another
- another acetyl coA binds to ACP
- condensation of malonyl coA and acetyl coA, releasing CO2 and forming acetoacyl ACP (2C)
Explain the process of reduction, dehydration and reduction in fatty acid synthesis
Reduction of acetoacyl ACP using NADPH Dehydration Reduction of the product using NADPH Repeated until the desired molecule is made Product is hydrolysed to release ACP
What is the role of fatty acid synthase in fatty acid synthesis
Catalyses all reactions except the 1st reaction
Composed of 7 smaller enzymes
Give the reaction for the synthesis of palmitate
acetyl coA + 7 malonyl coA + 14 NADPH + 14H+
->
palmitate + 7CO2 + 6 H20 + 8 coA + 14 NADP
Compare metabolism of fatty acids to synthesis of fatty acids
met - coA, FAD/NAD, mitochondrial matrix
syn - ACP, NADPH, cytoplasm
Give two examples of inborn errors of lipid metabolism
MCAD
Primary carnitine deficiency
What occurs in MCAD
Medium chain acyl coA dehydrogenase deficiency Required for the oxidation of acyl coA tested for via heel prick Autosomal recessive inheritance Fat cannot be burnt No fasting + increase glucose intake SIDS
What occurs in primary carnitine deficiency
unable to shuttle acyl coA
mutation in a gene that takes up carnitine
supplement or carnivore given
Autosomal recessive inheritence
How many carbons are in cholesterol
27
Give the overall mechanism for the synthesis of cholesterol
- Make IPP (isopentyl pyrophosphate)
- condense 6 IPP into squalene
- modification via cyclisation in the ER
Explain how IPP is made in cholesterol synthesis
cytoplasm
- 2x acetyl coA combined to form acetoacetyl coA via bet ketothiolase
- add another acetyl coA to form HMG-coA via HMG-CoA synthase
- reduction of the product to mevalonate via HMG-coA reductase and 2 NADH
- conversion of mevalonate by sequential phosphorylation and decarboxylation
What process in cholesterol synthesis is the target of statins
reduction of HMG-coA using HMG-coA reductase in the production of IPP
Explain how 6 IPPs are combined during cholesterol synthesis
cytoplasm
IPP + dimethylallyl pyrophosphate -> geranyl pyrophosphate (10C)
geranyl PP -> farnesyl PP (15C)
farnesyl PP x 2 -> squalene (30C)
Explain the process of cyclisation in cholesterol synthesis
ER
squalene is converted to squalene epoxide and then cyclase causes it to form lanosterol (methyl and hydride shifts)
19 step conversion from lanosterol to cholesterol + x3 demethylation
What is the significance of pregnenolone
building block for enzymes
All 5 steroid hormone classes derive from pregnenolone
What can cholesterol be used for
synthesis of pregnenolone synthesis of taurocholate
synthesis of glycocholate (primary bile salt) via breakdown
Where are bile salts synthesised and stored
synthesised in the liver and stored in the gall bladder
What are bile salts required for
fat and fat soluble vitamin digestion
Released into the SI to emulsify fats
a lack of bile salts = steatorrhea
How is vitamin D synthesiserd
7- dehydrocholesterol converted to pre vit D (UV) then converted to vit D then calcitrol
lack = ricketts
Where are lipid rafts found and what is their function
found in the plasma membrane
Used for movement of cell-surface receptors
Explain the process of absorption of triglycerides
- TAGs -> MAGs/DAGs + fatty acids via lipases
- emulsification by bile salts and addition of cholesterol -> mixed micelle
- mixed micelle passes through the intestine wall via enterocytes
- MAG + fatty acids -> TAGs
- TAGs incorporated into chylomicron with cholesterol and apoproteins
- enters lymphatic system via lacteal
Describe the structure of a chylomicron
core of TAGs, cholesterol esters
apoproteins on the surface
phospholipid monolayer with free cholesterol
hydrophobic core
What is the function of cholesterol acyltransferase
synthesis of cholesterol esters so they are more hydrophobic and pack more tightly
What are the 5 forms of lipoproteins
chylomicrons very low density lipoproteins (VLDL) intermediate density lipoproteins (IDL) Low density lipoproteins (LDL) High density lipoproteins (HDL)
What is the function of apoproteins
Act as receptors
Different apoproteins are taken up into different cells
What is the purpose of the chylomicron
Allows transport from the lymphatic system to the blood
lipoprotein enzyme recognises the apoprotein and breaks down the TAGs to form glycerol and fatty acids
What are lipoproteins
“leftovers” of the CM
Compare LDL to HDL
LDL - bad, takes cholesterol from the liver to peripheral tissue, leads to athersclerosis
HDL - good, takes cholesterol from peripheral tissues to the liver
What occurs in familial hypercholesterolaemia
Normally LDL is taken up by the liver via the LDL receptor by receptor mediated endocytosis
Mutant LDL receptor means LDL is left in circulation
Dominant inheritance
Atherosclerosis and heart attacks
Give some drugs used to treat familial hypercholesterolaemia
statins - inhibits HMG-coA reductase (lovastatin)
resins - inhibits absorption of bile salt and cholesterol in the small intestine by binding (cholestyramine)
What is the difference between ribosomes bound to the ER and free
free - proteins for cellular use
bound - for secretion or within plasma membrane or lysosome
Describe the synthesis of proteins and how they become free or bound
All ribosomes begin in a common pool
Translation of mRNA
protein produced has a signal peptide which directs the protein to the correct area in the cell
What happens to a protein with a signal peptide specific to the ER
translation halts
ribosome moves to the ER membrane
Translation restarts with the peptide entering the lumen
What happens to a protein with no signal peptide
ribosome remains in the cytoplasm
What happens to a protein that is compartment specific
ribosome remains
Protein moves to the compartment
Why are there multiple ribosome per peptide
1 ribosome = too slow
polyribosome used instead
What happens to incorrectly folded proteins
blocked form the ER exit
Exported and degraded
Which disorder is associated with membrane trafficking
cystic fibrosis
CTFR mutation means that chloride channels become affected which leads to CF
Explain the process of exocytosis
- vesicles containing protein which have been modified in the ER bud
- fusion with the golgi
- further modification (usually sugar addition)
- vesicle buds
- fusion with the palms membrane for secretion
What are the 2 types of secretion
constitutive vs regulated
C - all cells, steady stream of vesicles, from TGN, fuse with the membrane, replenishes the membrane
R - Excitable cells, concentrated products, stored in secretory vesicles until a signal stimulates secretion e.g. insulin release
Explain the process of endocytosis
- membrane invaginate and pinches off
- vesicle formation
- vesicle surrounded by clathrin which is removed after complete formation
- dynamic helps pinch from the membrane
What are the 3 types of endocytosis
Receptor mediator endocytosis
Pinocytosis (fluid intake)
phagocytosis
Describe gated transport
Import receptors around the nucleus recognise nuclear localisation signals on nuclear proteins
Movement is via nuclear pores
Describe vesicular transport
Proteins move between organelles via microtubules
vesicles bud on one organelle and move to fuse with others
How far apart do membranes have to be for fusion
1.5nm
What are the 3 types of intracellular transport
Gated transport
Transport across membranes
Vesicular transport
Give a disease associated with endocytosis
familial hypercholesterolaemia
LDL receptor is not produced or is not functional so LDL is not taken up leaving a high level in the blood
Give a disease associated with exocytosis
Cytic fibrosis
CTFR mutation leads to a deltaFSO8 mutation and degradation. Chloride channels being affected lead to CF
What does skeletal muscle and cardiac muscle rely on for energy
carb metabolism and fatty acid oxidation
What does the brain and nervous tissue rely on for energy
carb and ketone body metabolism (no fatty acids)
How are carbs stored
glycogen in the liver
What occurs to skeletal muscle during exercise, both light and heavy contraction
Large and rapid increase in ATP demands
light - ATP consumption = oxidative phosphorylation
heavy - ATP consumption > oxidative phosphorylation
glycogen store breaks down
lactate is transported to the liver and then remade into pyruvate
Why must the amount of glucose in the brain be carefully controlled
hyperglycaemia - irreversible dameg
hypoglycaemia - faintness and coma
What does the heart use for energy
TCA cycle substrates e.g. fatty acids and ketone bodies
Give the metabolic features of the liver
highly metabolically active
can interconvert nutrients
glucose storage
lipoprotein metabolism
What are the metabolic responses to eating
Increase in insulin from eh beta cells in the pancreas
Increase in glucose uptake
Increase in glycogen synthesis
Increase in glycolysis
What are the metabolic responses to short term fasting
pancreas secretes glucagon from the alpha cells of the pancreas
Gluconeogenesis
Glycogenolysis
What are the metabolic responses to prolonged fasting
pancreas secretes more glucagon
when the glycogen store runs out, gluconeogenesis occurs
Explain the process of gluconeogenesis and what can it be used for
uses 4 ATP (G=-38)
pyruvate -> oxaloacetate -> phosphophenol pyruvate -> fructose-6-p -> glucose
glycogenic amino acids from the TCA
glycerol
Lactate
Describe aerobic respiration
ATP demands can be met by oxidative phosphorylation using glucose and other fuels
What is the effect of adrenline
rate of glycolysis increases
muscle glycolysis increases
liver gluconeogensis increases
increase in lipolysis in adipocytes
Describe anaerobic respiration
ATP demands > oxygen delivered
glycogen breaks down in muscle
increase in lactate
liver converts lactate to glucose
Describe product inhibition
as levels of product increases, the rate of reaction decreases
What are the 2 forms of hexokinase
HK1 in muscle and HK IV in the liver (sensitive to glucose)
Which hormones increase blood glucose
Glucagon
Adrenaline
Glucocorticoid (cortisol) (increases enzymes concerned with glucose availability)
Which hormone decreases blood sugar
Insulin
What are the 2 types of diabetes
type 1 - beta cell dysfunction, not enough insulin
type 2 - insulin resistance
What does Diabetes lead to
hyperglycaemia diabetic retinopathy nephropathy neuropathy increase in fatty acids and lipoproteins increase in ketone bodies -> acidosis risk increases
