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year 2 sem 1 > Wk 2/3 - GI(metabolism:''''() > Flashcards

Wk 2/3 - GI(metabolism:''''() Flashcards

1
Q

ATP

A

nucleotide

  • nitrogen containing base attached to ribose sugar and 3 phosphates
  • 3rd Pi hydrolysed off to make energy and form ADP
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2
Q

standard free energy and actual free energy of ATP

A

standard - -31kj/mole

actual - 60kj/mole

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3
Q

how efficient is ATP usage

A

40%

- so actual energy gain is about 24kj/mole

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4
Q

NADP

A

NICOTINAMIDE ADENINE DINUCLEUTIDE PHOSPHATE

  • Nicotinamide ring reduced to dihydro-nicotinamide
  • A hydrogen carrier
  • Exists in an oxidised state and a reduced state
  • Carries 2 electrons from 2 hydrogens
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5
Q

role of NADP

A
  • Currency of reducing power (it’s reduced)

Pathways that reduce it

  • > Pentose phosphate pathway
  • This is a Glucose metabolism pathway
  • Glucose is partially oxidised liberating CO2
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6
Q

how is reduced NADP re-oxidised

A

via biosynthetic pathways…

  • fatty acid and cholesterol synthesis
  • DNA synthesis
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7
Q

glucose energy store

A
  • Small amount circulating in plasma
  • Glucose can be used by all tissue
  • But small concentration of glucose (not a lot of energy stored in circulating glucose)
  • Glycogen stores glucose
  • This is stored in Liver and muscle
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8
Q

glycogen energy store

A
  • It can be mobilised very quickly
  • It can be metabolised anaerobically (don’t need to increase breathing rate as no CO2 produced)

Disadvantages

  • It’s hydrated
  • Weight is limited by the fact ¾ of the weight will be water
  • So stores of glycogen relatively small
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9
Q

tricylglycerol energy store

A
  • Highly reduced
  • Very high energy yield
  • Not hydrated so no weight penalty
  • Largest energy store in the body

Disadvantage
- Since it’s fully reduced it needs O2 to be metabolised

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10
Q

protein energy store

A
  • When broken down it can be converted to intermediates which can be metabolised
  • Either used to yield glucose or ketone bodies
  • Not a very high energy output per gram

Disadvantage…

  • There isn’t any storage protein
  • All the protein is functional
  • When you break down protein you Lose function (enzyme or plasma protein etc)
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11
Q

glycogen breakdown

A

glucose phosphate
- metabolized in the glycolytic pathway

AEROBIC directly metabolized to pyruvate and further oxidised to acetyl CoA and further in the mitochondria

ANAEROBIC
pyruvate reduced to lactate

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12
Q

tricylglycerol breakdown

A
  • Main storage of fat
  • Lipolysis releases free fatty acids into plasma
  • These are taken up by tissues – muscle, heart, kidney
  • And oxidised in the beta-oxidation pathway to acetyl-coenzyme A
  • Fatty acids can’t be taken up by the brain
  • Except in starvation when conc. Of free fatty acids rise acetyl CoA can be diverted to ketone bodies
  • These are then circulated and used by tissue –(muscle, heart etc AND BRAIN)
  • Ketone body production only in liver
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13
Q

protein breakdown

A
  • Broken down by proteolytic enzymes to release amino acids
  • 20 amino acids in proteins
  • Each diff. breakdown pathways
  • Some can be converted to glucose, called GLUCOGENIC
  • Others can’t so end up as acetyl CoA, called KETOGENIC
  • During starvation they can inc. prod. Of ketone bodies
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14
Q

acetyl- CoA

A

many fuels end up as this

  • it’s the principal fuel in the terminal oxidation pathway
  • also known as tricarboxylic acid cycle
  • in this cycle acid groups completely oxidised to CO2 which generates a lot of ATP but requires O2
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15
Q

properties of mobilised glucose

A
  • Circulates in plasma
  • Conc. Maintained in tight levels -> glucose homeostasis
  • If it gets low the brain notices this (25% of energy spent on brain)
  • If it gets high – dangerous as glucose reactive (reacts with proteins and vasculature etc)
  • So when glucose rises after feeding its brought down quickly by storage
  • In diabetes glucose can get high
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16
Q

properties of mobilised fatty acids

A
  • Not very soluble
  • In plasma mostly bound to albumin
  • During the fed state – free fatty acid in plasma pretty low
  • Rises quickly during fasting (overnight or prolonged)
  • Never gets above 2mmol/L
  • And turned over very quickly
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17
Q

properties of mobilised ketone bodies

A
  • Only one of thems a ketone
  • Acetoacetate and 3-hydroxy butyrate derived from acetyl-CoA from fatty acid breakdown
  • Conc. Low at fed state and increase during fasting
  • Circulate and used as fuel by heart, muscle, kidney etc AND BRAIN
  • High levels of ketone bodies vv dangerous as they’re strong acids so cause acid imbalance METABOLIC ACIDAEMIA
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18
Q

properties of mobilised amino acids

A
  • 20 diff acids in varying conc.

- Overall conc. Doesn’t change vv much but balance between them may during fasting

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19
Q

properties of mobilised lactate

A
  • Prod. By eg muscle anaerobically oxidising glucose or in RBC
  • Circulates at low levels
  • Used to fuel lots of tissues
  • Anaerobic muscle exercise inc. concentrations
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20
Q

different types of muscle fibres - what are they for

A

type 1 - aerobic energy prod

type 2 - anaerobic energy prod.

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21
Q

creatine phosphate

A
  • Creatine phosphate is a small energy store within the muscle
  • Muscle relatively high conc. Of ATP
  • Creatine phosphate higher than this
  • Creatine phosphate has an attached phosphate group that can be transferred to ADP – RELEASING CREATINE
  • As ATP is hydrolysed to ADP by myosin ATPase it can be re-phosphorylated back to ATP
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22
Q

fuels for the 2 diff. types of muscle

A

purely anaerobic (type 2)

  • muscle ATP
  • creatine phosphate
  • muscle glycogen

purely aerobic (type 1)

  • ATP, creatine-P, glycogen
  • fatty acids (muscle and adipose tissue)
  • plasma glucose (from liver glycogen and gluconeogenesis)
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23
Q

what stimulates glycogen breakdown?

A

glucagon, adrenalin, increase conc. of AMP

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24
Q

what are the intermediates between glucose and lactose in glycolysis

A
  • glucose broken down to glucose-1-phosphate
  • glucose-1-phosphate isomerized to glucose-6-phosphate
  • which is broken down anaerobically to pyruvate
    pyruvate reduced to lactate

1 molecule of glucose…

  • generates 2 ATP
  • yields 2 lactate
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25
Q

what are the steps of glycolysis from pyruvate if there’s O2 present

A
  • pyruvate enters mitochondria to be oxidised to acetyl-CoA
  • acetyl-CoA enters the TCA cycle
  • generates ~30 ATP
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26
Q

what happens to lactate

A
  • Enters plasma and circulates
  • In some tissues converted back to glucose via gluconeogenesis (mostly LIVER), also kidney
  • Essentially a reversal of glycolytic pathway
  • Glucose then released into plasma and used by the muscle
  • Requires 6ATP
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27
Q

distribution of fuels used during exercise

A

Start of exercise

  • Most energy from muscle stores
  • These are quickly depleted

then

  • Energy supply taken over by non-esterified fatty acids in the plasma
  • From mobilization of fat in adipose tissue

Then

  • Plasma glucose plays increasing part
  • From breakdown of liver glycogen and gluconeogenesis

Prolonged exercise

  • NEFA principle fuel
  • Ceiling of about 70—75% unclear why
  • How quickly fatty acids can be transported???
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28
Q

control of metabolism during exercise

A
  • During exercise ATP -> ADP
  • Topped up by creatine phosphate
  • This runs out
  • ADP further utilised by a dismutation reaction catalysed by enzyme called adenylate kinase or myokinase to give AMP and ATP
  • Essentially ATP broken down into ADP and then AMP
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29
Q

adenine nucleotide concentrations during exercise

A
  • During exercise although ATP is used up the product is AMP

Consequence of this…

  • AMP acts as a control feature
  • Through the enzyme AMP-activated protein kinase

A lot of metabolic pathways controlled by phosphorylation/ dephosphorylation of regulatory enzymes

  • Enzyme that transfers a phosphate from ATP to something else is a KINASE
  • Other hormonal signals can activate phosphatase’s which remove the phosphates
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30
Q

AMP-protein kinase functions

A
  • controls kinases
  • also phosphorylates lots of regulatory enzymes

an inc. in AMP-protein kinase activates processes such as…

  • glucose uptake
  • glycolysis
  • fatty acid oxidation
  • mitochondrial biogenesis

these processes are needed during energy demand
- inhibits processes that happen normally during feeding

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31
Q

net protein utilization (NPU)

A
  • Quantifies nutritional value of protein
  • Fractional incorporation of amino acids into body protein
  • A measure of ability of protein to sustain growth

Def.
(Wt. amino acids incorporated into protein) divided by (wt. amino acids supplied in diet)

Vegetables tend to have lower NPU

  • Veg doesn’t have lower protein content
  • But veg has diff. protein values
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32
Q

2 main types of amino acids

A

essential - cannot be synthesised within the body do must be supplied in the diet
non-essential - can be synthesised from other amino acids in the diet

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33
Q

list of essential amino acids

A
  • Isoleucine
  • Leucine
  • Lysine
  • Methionine
  • Phenylalanine
  • Threonine
  • Tryptophan
  • Valine

Some are a combo

  • Arginine
  • Histidine
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34
Q

what does it mean if a protein has a high NPU

A

it’s high in essential amino acids

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35
Q

kwashiorkor protein malnutrition

A
  • Children having a body weight between 60-80% of that expected of that age
  • Protein mal. Effects children more as they have high protein requirement
  • Total energy intake is adequate but not enough protein

Leads to swollen bellies

  • Oedema due to albumin deficiency
  • Enlarged liver
  • Muscle wasting
  • Diarrhoea
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36
Q

marasmus protein deficiency

A
  • More severe
  • Body weight less than 60% of expected value
  • Protein and calorie deficiency
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37
Q

degradation of extracellular proteins

A
  • If become damaged they are degraded by endocytosis…
  • Damaged cell binds to receptor
  • Cell and receptor are Internalised (endocytosis)
  • Form a closed compartment in the cell (endosome)
  • Has a membrane with protein inside the membrasome
  • Membrasome then fuse with lysosomes (degrative)
  • Lysosomes have low ph
  • Contain degradative enzymes
  • Degrade captured protein
  • This liberates amino acids inside the cell
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38
Q

degradation of intracellular proteins

A
  • Recognised for degradation and tagged by attachment at c terminal by several molecules of UBIQUITON
  • Label for degradation
  • Degradation carried out by proteosome
  • ATP dependant
  • Protein enters cavity in proteosome and is degraded to release amino acids
  • Ubiquitin is spared and reused
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39
Q

degradation of dietary proteins

A
  • Degraded in digestive tract
  • Starting in the stomach
  • GASTRIC PIT
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40
Q

cells of the gastric pit

A
  • Chief cells -. Produce degradative enzymes
  • Parietal cells – lower ph in gastric lumen
  • Mucus cells
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41
Q

parietal cells structure - apical side/ gastric lumen

A

so in the gastric lumen…

  • high protein conc.
  • ph 0.8
  • acidified

gastric ATPase

  • a proton pump that hydrolyses ATP
  • pumps protons into gastric lumen in exchange for potassium ions
  • makes the gastric lumen really acidic
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42
Q

parietal cells structure - basolateral side/ plasma

A

so on the plasma side…

  • low protein conc.
  • ph 7.4
  • alkalified

anion transporter

  • protons come from carbonic acid (formed by hydration of CO2)
  • carbonic acid ionised to bicarbonate
  • bicarbonate is v alkaline so its exported into plasma in exchange for chloride ions
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43
Q

drugs that affect parietal cells in the gastric pit

A

omeprazole and vonoprazan

  • inhibit gastric ATPase
  • used to treat gastric ulcers
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44
Q

why is the stomach acidified?

A

inhibits bacteria growth

denatures dietary proteins

  • unfolded
  • more easily hydrolysed by proteolytic enzymes in digestive tract

not essential though

  • if secretion of hydrofluoric acid fails not a lot of consequences
  • except vitamin B12 is uptake by intrinsic factor
  • if don’t have a stomach you need injections of B12
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45
Q

what uptakes vitamin B12

A

intrinsic factor

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46
Q

whats the principal degrading enzyme in the stomach

A

pepsin

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47
Q

pepsin

A
  • secreted by chief cells
  • synthesis of degradative enzyme is hazardous for cell
  • bc/ if enzyme was active it would degrade cell itself
  • so enzymes are secreted as inactive precursors called ZYMOGENS
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48
Q

the excretion of pepsin

A
  • Synthesis begins with protein made in cytoplasm -> lumen of endoplasmic reticulum -> golgi apparatus -> secretary vesicles
  • Contained within vesicles
  • Under appropriate stimulus these vesicles fuse with plasma membrane of cells and release pepsinogen into lumen of stomach
    This is called REGULATED EXOCYTOSIS
  • HCl turns pepsinogen into pepsin activating it
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49
Q

how is pepsinogen activated

A
  • when it encounters hydrogen ions in the stomach (low pH)
  • causes spontaneous breaking of bond which changes structure of pepsinogen (activates it)
  • pepsin can catalyse this process - AUTOCATALYSIS
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50
Q

function of pepsin

A
  • Recognises large hydrophobic amino acid
  • Doesn’t hydrolyse every bond in protein
  • Pepsin degrades to fairly large peptides
  • These are then further degraded by other enzymes
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51
Q

next stage of degradation after stomach/ pepsin

A
  • further down the digestive tract
  • content of stomach neutralised by pancreatic secretion
  • pancreas secretes high levels of bicarbonate which lowers the pH
  • contains a series of proteinases
  • also degradative enzymes that work on fat and carbohydrate
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52
Q

cascade of activation of pancreatic proteases

A

like pepsin they’re secreted as inactive precursors

activation cascade…

  • TRYPSIN IS KEY
  • trypsinogen and enteropeptidase secreted into digestive tract
  • enteropeptidase activates trypsinogen (changes to trypsin) and other proteinase precursors
  • activation cascade triggered too early - degradation of cells (PANCREATITIS)
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53
Q

what inhibits pancreatic proteinases?

A

trypsin inhibitor
- binds to active trypsinogen to deactivate it
so first molecule of trypsinogen are deactivated
- later on inhibition swamped by activation and trypsin made

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54
Q

outcome of protein digestion

A
  • Amino acids taken up into intestinal cells together with sodium ion
  • By co-transporters which recognise diff. amino acids
  • If peptides left over further degraded by peptonises or taken up and degraded by cells
  • Amino acids leave cells and enter blood stream
  • Free amino acids in the blood transported around and taken up by cells for protein synthesis
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55
Q

first stage of amino acid metabolism

A

transamination
- Catalysed by transaminases
- Amine group NH3 is transferred from amino acid onto oxoglutarate
- So amino acid is turned into an oxo-acid
- This carbon backbone/ oxo-acid is further metabolised (eg to glucose or fatty acids)
- amine group transferred to a diff. amino acid – GLUTAMATE
(so amino group removed and is present in glutamate)

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56
Q

stage 2 of amino acid metabolism

A

oxidative deamination

  • Amino group removed from glutamate by glutamate dehydrogenase
  • Oxidises the glutamate (by reduction of coenzyme NAD)
  • Amino group liberated as ammonia
  • In this process NAD is reduced to NADH
  • ammonia enters urea cycle in the liver = urea
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57
Q

ammonia features

A
  • Ammonia is toxic to central nervous system
  • If ammonia builds up reaction stops
  • Ammonia inhibits the TCA cycle
  • So its important to remove the ammonia (removed as urea)
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58
Q

hows are amino acids excreted through urea?

A

Then excreted through urea as follows…

  • Transamination reaction to form glutamate
  • Glutamate can release its ammonia
  • Make carbamyl phosphate
  • Carbamyl phosphate incorporated into urea cycle
  • Urea cycle only in liver – partly in mitochondria, and cytoplasm
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59
Q

what does ammonia form upon reaction with CO2

A

carbamyl phosphate

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60
Q

what happens when carbamyl phosphate reacts with ornithine in the urea cycle

A
  • carbamyl phosphate transfers its amino group onto it to form citrulline
  • Citrulline can receive another amino group from aspartate and cycle continues etc etc
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61
Q

where does carbamyl phosphate enter into the urea cycle?

A
  • between ornithine and citrulline
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62
Q

how is amino acid transported from peripheral tissues to the liver

A
  • it’s not glutamate that’s transported – it’s ALANINE
  • Glutamate formed by transamination
  • Can be transaminated with pyruvate to form alanine
  • Alanine can then enter the plasma and circulate
  • Be taken up by the liver
  • And back-transaminated to glutamate
    (a device for carrying amino groups from glutamate in tissues to glutamate in the liver)
  • So conc. Of alanine in the plasma rises when there’s peripheral amino acid breakdown
  • Particularly during starvation
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63
Q

properties of urea

A
  • Very soluble in water
  • Electrically neutral – neither acidic nor base
  • Contains 48% N by weight (protein contains ~16%)
  • Synthesised in liver, not further metabolised
  • Normal plasma conc. 2.5-7 mmol/l
  • rises renal failure (uraemia)
  • falls in liver cirrhosis (or deficiencies in the urea cycle enzymes)
  • ammonia toxic to central nervous system
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64
Q

other routes of ammonia secretion (other than urea)

A
  • directly through the kidneys
  • in tissues ammonia liberated by glutamate dehydrogenase
  • glutamine can transfer through the plasma to the kidneys
  • where glutaminase takes the amino-group off again (or amido group) to form ammonia
  • liberated directly into the urine through the kidneys
  • system is important during starvation
  • no intermediate formation of urea
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65
Q

oxo-acids

A
  • if oxo-acid broken down into acetyl-CoA amino acid is ketogenic
  • if oxo-acid… into TCA cycle intermediate it’s glucogenic
  • bc/ it can be converted back to glucose
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66
Q

one-carbon metabolism

A
  • glycine is not glucogenic or ketogenic it’s part of the one carbon pathway
    One carbon pathway
  • single carbon fragments from amino acids are broken down and metabolised
  • glycine, serine, histidine, tryptophan all contributes single carbons
  • metabolized by attaching to tetrahydro-folic acid
  • folic acid is a vitamin supplied by diet or bacteria
  • reduced twice to be used as a co-enzyme to…
  • dihydrofloric acid
  • tetrahydrofolic acid
    -tetrahydrofolic acid can be oxidised and reduced to methylene-tetrahedrafolic acid (further reduced to methyl-tetrahedrafolic acid)
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67
Q

one-carbon pathway important in synthesis of..

A
  • purine (carbons come from one carbon metabolism)
  • thymine (methyl group from…)
  • methionine (methyl group from…)

so, essential in…

  • DNA/RNA synthesis
  • mitochondria synthesis
  • etc
68
Q

why is one-carbon metabolism dependant on B12?

A
  • Vitamin B12 transfers methyl group onto methionine
  • So if B12 deficiency then methyl-tetrahydrofolate accumulates
  • Whole pathway seizes up
  • In anaemia, cells in stomach fail to secrete intrinsic factor in stomach and vit. B12 not absorbed
  • Overall effects DNA replication particularly in rapidly dividing cells
69
Q

dihydrofolate reductase inhibitors\

A
  • called anti-folate drugs

CYCLOGUANIL is an inhibitor of dihydrofolate reductase
- Component of antimalarial drug malerone

Methotrexate

  • Anti-tumour drug
  • Analogue of folic acid
  • Inhibits dihydrofolate reductase

SULFONAMIDES (antibiotic)

  • Works in bacteria
  • Vv simple
  • Sulfonamides mimic nitrogen groups where one-carbon atoms attach
  • And so acts as an inhibitor of folic acid synthesis in bacteria
70
Q

carbon links between 2 sugars can be…

A

below the plain of the ring -> alpha

above the plain of the ring -> beta

71
Q

starch

A
  • Major form of carb in the diet
  • Principle storage polysaccharide in plants
  • Glucose units joined together

2 components within starch…

Amylose

  • 10-20%
  • Formed by linking glucose units between carbon 1 and 4
  • Alpha 1-4 link
  • Straight chains

Amylopectin

  • 80-90%
  • Only glucose
  • Straight chains with alpha 1-4 links
  • Also contains branches
  • Carbon 1 in one chain links to carbon 6 of another
72
Q

enzymes in starch digestion

A
  • alpha-amylase
  • glucoamylase
  • isomaltose
73
Q

alpha-amylase

A
  • In saliva (levels variable)
  • Also secreted in the pancreas
  • Hunter gatherers have lower levels than agriculture populations (evolutionary)
  • Endoglycosidase – hydrolyses a(1-4) links
  • Products are oligosaccharides
  • A few sugars linked together
  • Short and straight or branches
74
Q

glucoamylase

A
  • Present on luminal side of intestine wall

Deglycosylase -> hydrolyses a(1-4) links in…

  • Oligosaccharides
  • Trisaccharide’s
  • Maltose
  • Not alpha 1-6 links
75
Q

isomaltose

A
  • Present on luminal side of intestinal wall

- Hydrolyses a(1-6) link in maltose

76
Q

what are the products of starch degeneration

A

maltose and isomaltose

77
Q

maltose

A
  • alpha 1-4 links -> hydrolysed by glucoamylase

- alpha 1-6 links -> hydrolysed by isomaltase

78
Q

lactose

A
  • contains galactose linked beta 1-4 to glucose
  • won’t be hydralysed by amylase
  • hydrolyzed by intestinal enzyme -> lactase (/ beta-galactosidase)
  • hydrolyses lactose to galactose and glucose
79
Q

lactose intolerance

A
  • caused by low levels of lactase
  • widespread natural sit.
  • Lactose is a mil disaccharide
  • Lactase expressed highly in young children but is normally shut down in adulthood
  • So adults usually have low levels of lactase
  • And so if adults drink milk etc it isn’t digested by small intestine, Instead ingested by large intestine by bacteria
  • Causing gas, digestive problems, diarrhoea
  • If adults are able to eat lactose, it’s due to a mutation
80
Q

sucrose

A
  • Contains glucose and fructose, linked alpha 1-2

digested by SUCRASE – intestinal enzyme

  • Same complex as isomaltose – sucrase/isomaltase
  • Quite large component of many diets
  • Interest in artificial sweeteners which mimic sucrose

SUCRALOSE

  • artificial sweetener
  • Hydroxyl groups replaced by chloride
  • Molecule cannot be hydrolysed by sucrase
  • It’s excreted
  • But tastes sweet

SACRASE breaks sucrose into glucose and fructose and these are individually taken up

  • If there’s sucrose in the blood that’s a bad sign
  • Maybe a stomach ulcer?
81
Q

non hydrolyzable polysaccharides

A
  • Roughage
  • Plant polysaccharides so not attacked by mammalian digestive enzymes
  • Degraded by bacterial enzymes a bit
82
Q

active transport of glucose into the intestine

A
  • Creation of sodium ion gradient by ATPase
  • Gradient of sodium between intestine and inside of cell
  • Source of energy for uptake of glucose
  • 1 glucose and 2 sodium
  • Sodium running down conc. Grad
  • Glucose runs up

then. ..
- Glucose can run downhill to lower conc. in plasma
- Through uniporter – GLUT 2

83
Q

oral rehydration therapy

A
  • Combating loss of water by inc. conc. Of sodium ions in the body
  • By exploiting the glucose transporter
  • So use glucose and salt mixture
  • Glucose promotes sodium ion uptake
  • Which expands the plasma and retrieves water
84
Q

levels of glucose after feeding

A
  • glucose quickly rises following a meal
  • this rise is detected by the endocrine pancreas -> secretes INSULIN

insulin rises very sharply and promotes uptake of glucose into…

  • fat
  • muscle
  • insulin affects glucose utilization in the liver
  • doesn’t directly impact glucose transport into the liver

increase in insulin also lowers the conc. Of NEFA (non-esterified fatty-acids) in the plasma

  • because it inhibits lipolysis
  • after feeding fatty acids dec. then gradually inc. As digestions completed
85
Q

once glucose is in the plasma…

A
  • circulates and is taken up by various types of cell
  • these cells don’t have to carry out active transport
  • as glucose conc. in plasma is higher than in the cell
  • therefore, glucose runs straight in (passively)
86
Q

types of glucose transporters

A

GLUT1 in body tissues

  • Km value of 5 millimolar
  • Km value = conc. To give half the maximum rate of transport

GLUT2 in liver, kidney, intestine, pancreas

  • higher Km
  • so, it keeps transporting glucose at high levels of plasma glucose
  • continuous transport into cells as plasma conc. Inc.

GLUT3 in brain

  • low Km
  • close to saturation whatever the glucose plasma conc.
  • Therefore glucose uptake in brain is pretty much continuous
  • Good bc/ wouldn’t want brain to be dependent on rate of glucose production by digestion

GLUT4 in muscle adipose and heart

  • Insulin responsive
  • Insulin inc. amount of GLUT4 in these tissues
  • Responsible for insulin dependent uptake after feeding
  • (feeding inc. plasma glucose and insulin conc, and insulin inc. uptake of glucose)

SGLT1 in duodenum, jejunum, kidney
- Taking glucose up from extracellular space into the body

87
Q

what happens to glucose once it’s taken up by liver cells

A
  • Have an Uptake system designed to cope with high conc. Of glucose
  • (Glucose up-taken in intestine and first tissue it meets through portal system is the liver)

Firstly

  • PHOSPHORYLATED
  • Phosphorylated on carbon 6 by phosphate on ATP
  • Forms glucose-6-phosphate (starting point for metabolism)
  • All tissues contain HEXOKINASE which catalyses this reaction
  • Hexokinase has vv low Km for glucose
  • Liver contains GLUCOKINASE
  • Higher Km
  • Unusual kinetics -sigmoidal saturation curve
  • Can continue to work at vv high glucose conc
88
Q

the metabolic fates of glucose

A

Converted to glycogen

  • Involves isomerization of glucose-6-phosphate to glucose-1-phosphate
  • Transfer reaction with UTP to make UDP-glucose (glucose attached to UDP)
  • UDP-glucose is the precursor of glucose in glycogen
Glycolytic breakdown (glycolysis)
- Glucose-6-phosphate converted to pyruvate or lactate (aerobic or anaerobic)

Pentose-phosphate pathway
- Generates 5 carbon sugars and reduced co-enzymes

89
Q

glycogen

A
  • A polymer of glucose
  • Contains only glucose
  • Same structure as starch
  • Glucose chains linked alpha 1-4 (some alpha 1-6)
  • End with free carbon-1 -> reducing end
  • End with carbon-4 free -> non-reducing end
  • Because of structure only one reducing end and then 1,6 branches and lots of non-reducing ends
  • Non-reducing ends are where glucose is hydrolysed off or added
  • Non-reducing end attached to a protein (GLYCOGENIN)
  • Lots of branches (up to 12 layers) forming a big particle with a 40 nanometre diameter
  • Contains ~50,000 glucose units
  • ~2000 non-reducing ends so glucose can be added or hydrolysed off
90
Q

what does glycogen synthase do

A

transfers glucose from UDP-glucose to glycogen

  • activated by insulin
  • insulin promotes glycogen synthesis in the liver and muscle
91
Q

glycogen phosphorylase

A
  • Activated by various hormones
  • Adrenalin in muscle
  • Glucagon in liver
  • So these 2 inhibit glycogen synthesis and promote glycogen breakdown

Inhibited by INSULIN

  • So insulin stimulates glycogen synthesis and inhibits glycogen breakdown
  • Enzymes controlled by phosphorylation and dephosphorylation reactions
  • Eg so adrenalin promote phosphorylation of glycogen phosphorylase (making it active)
92
Q

glycolysis

A

starts as glucose 6-phosphate
phosphorylated to fructose bisphosphate
- (catalysed by phosphofructokinase) -> important control step in the pathway

Fructose bisphosphate split into 2 3-carbon phosphor-sugars

  • Each of these oxidised and can generate 2 ATP
  • Catalysed glyceraldehyde phosphate dehydrogenase
  • Reduces NAD to NADH
  • Incorporates phosphate into intermediate -> bisphosphoglycerate
  • Which can transfer a phosphate to ADP and form ATP

Further along on pathway is intermediate phosphoenolpyruvate
- Which can be converted to pyruvate to generate ATP

93
Q

balance of ATP in anaerobic glycolysis

A
  • Each 3-carbon fragment produces 2 ATP
  • So a glucose molecule produces 4 ATP
  • Need 1 ATP for phosphofructokinase reaction

So if glucose comes from glycogen…

  • No ATP needed to breakdown glycogen
  • Consumes 1 ATP
  • Overall net balance 3 ATP per glucose

If it comes from free glucose

  • Another ATP is required for hexokinase/ glucokinase reaction
  • So 2 ATP consumed, 4 produced
  • Overall net gain 2 ATP per glucoseq
94
Q

what happens to pyruvate

A

end-product of glycolysis

  • pyruvate may be reduced to lactate
  • by reoxidation by reduced NAD generated earlier in the pathway
  • becomes self-sufficient de-mutation reaction
  • > glucose converted to 2 lactates
  • > with production of 2 ATPs
  • pyruvate may also enter the mitochondria and be metabolised to CO2
  • produces a lot more ATP
95
Q

anaerobic glycolysis

A

Anaerobic conversion of glucose to lactate is important in muscle during anaerobic exercise

  • So ATP can be generated quickly without inc. oxygen
  • Also important in cells eg RBC that have no other kind of ATP production
96
Q

gluconeogenesis

A
  • Only takes place in the liver and kidney
  • Replenishes plasma glucose from use of other precursors
  • Brain has large daily demand of glucose

How does gluconeogenesis produce glucose?

  • Pyruvate -> oxaloacetate -> phosphoenolpyruvate
  • Consumes one ATP and one GTP (essentially 2 ATPs)
  • The 2 phosphorylation reactions are also reversible
  • Phosphate hydrolysed off
  • Therefore, entire pathway from pyruvate to glucose is reversible

Except step from pyruvate to acetyl CoA is irreversible
- Acetyl coA cannot be converted to glucose (so fat can’t be converted to glucose)

97
Q

precursors of glucose

A
  • Lactate which comes from anaerobic glucose metabolism
  • Glycerol from breakdown of triacylglycerol
  • Gluconeogenic amino acids (during protein degradation or during starvation) Converted to intermediates eg pyruvate, oxaloacetate etc which can be converted to glucose
98
Q

controls of gluconeogenesis

A

Hormonally

  • Inhibited by insulin
  • Promoted by glucagon

Glucagon inhibits forward action at pyruvate kinase
- Promotes fructose bisphosphotase

99
Q

pentose-phosphate pathway background info

A
  • Present in many types of cell
  • Particularly Present in cells where fat/cholesterol synthesis are going on
  • Liver, adipose tissue, mammary gland etc, RBC
  • Produces reduced co-enzyme NADPH
  • Functions in reductive biosynthetic pathways
  • And anti-oxidative function
  • Present in cytoplasm
100
Q

pentose-phosphate pathway steps

A
  • Glucose 6-phosphate oxidised to 6-phosphategluconate
    (with the reduction of NADP to NADPH)

6-phosphategluconate oxidised by diff. dehydrogenase

  • Produces 5-carbon sugar RIBULOSE 5-PHOSPHATE
  • Loss of carbon dioxide

2 molecules of reduced NADP per glucose are produced

Ribulose 5-phosphate can be isomerised to other sugars
- It’s needed for DNA and RNA synthesis

Carbons are shuffled around to regenerate 6-carbon sugars and feed into beginning of pathway
Done through…
- TRANSKETOLASE -> takes 2 carbons from one sugar and adds them to another
- TRANSALDENASE -> moves 3 carbons

101
Q

pentose-phosphate pathway products/ actions

A

Reduced NADP required for
- Reductive synthesis eg fat synthesis, cholesterol synthesis

Anti-oxidative

  • In RBC lipid peroxidation is a hazard
  • Lipids oxidised to peroxides by reaction with oxygen

peroxides are reduced by a tripeptide called GLUTATHIONE…

  • this reduces peroxides to hydroxy compounds
  • glutathione becomes oxidises to a disulphide
  • the disulphide is reduced back to glutathione by reduced NADP
  • so important function of ^ pathway in RBC is to protect against oxidative damage
102
Q

glucose 6-phosphate dehydrogenase deficiency

A
  • widespread deficiency of glucose 6-phosphate dehydrogenase
  • most common genetic disorder in humans
  • x-linked (so males effected more)
  • in mutations glucose 6-phosphate dehydrogenase has LOW activity
  • so haemoglobin gets cross linked and RBC undergone haemolysis
  • exacerbated by drugs etc antibiotic and broad beans
  • name of this deficiency if FAVISM
103
Q

metabolism of fructose

A
  • from hydrolysis of sucrose
  • sucrose isn’t taken up in intestine, but fructose is
  • fructose can be taken up by cells
  • rarely phosphorylated by hexokinase and straight into glycolytic pathway
  • but glucose competes and so not vv. much
  • in liver there’s a special enzyme for fructose phosphorylation -> FRUCTOKINASE
  • phosphorylates fructose to fructose 1 - phosphate
  • then metabolized by glycolysis
  • 3-carbon sugars fed into glycolytic pathway
  • Fructose escapes control on glycolytic pathway
  • Which is why high fructose diets lead to fat
104
Q

deficiency of fructose 1-phosphate aldolase

A
  • Build-up of fructose 1-phosphate
  • Leading to fructose intolerance
    So inhibitions of…
  • Glycogen breakdown
  • Gluconeogenesis
  • Oxidative phosphorylation
    Resulting in…
  • Hypoglycaemia and lactic acidaemia
105
Q

metabolism of galactose

A
  • Metabolised in liver by galactokinase
  • Which phosphorylates galactose to galactose 1-phosphate
  • Which is then epimerized to glucose 1-phosphate
  • By first being transferred to UDP
  • And then an epimerase acting on UDP-galactose
  • Converting it to UDP-glucose
106
Q

alcohol metabolism

A
  • Most ethanol oxidation goes on in the liver
  • Ethanol oxidised by NAD to ethanal
  • Ethanal oxidised to ethanoic acid
  • This is convertible to acetyl CoA
  • Precursor of fatty acids or ketones
  • Or oxidised in TCA cycle
107
Q

aldehyde dehydrogenase

A

2 isoforms of this enzyme

  • 1 in mitochondria (low Km value)
  • 1 in cytoplasm (high Km value)
  • Widespread mutations in mitochondrial one
  • Inactivates it
  • Means alcohol doesn’t oxidate all the way to ethanoic acid
  • results in build-up of high conc. Of ethanal
  • side effects of nausea etc…
  • ALCOHOL INTOLERANCE
108
Q

disulfiram/ antabuse

A
  • Used to inhibit aldehyde dehydrogenase
  • Used as aversion therapy to treat alcoholism
  • Bc if you drink on this ethanal builds up leading to discomfort
109
Q

other alcohols metabolised

A
  • Alcohol dehydrogenase is a non-specific enzyme
  • Oxidise a lot of alcohol (some toxic)

Eg methanol

  • yields formaldehyde
  • Reactive with nucleic acids etc – DAMAGE

Eg ethylene glycol (found in antifreeze)

  • Oxidised to glyoxal and onto oxalic acid
  • Oxalic acid precipitates calcium in the kidneys – DAMAGE

Metabolism of toxic alcohols can be inhibited

  • By infusing ethanol to act as a competitive substrate
  • Or drug called fomepizole (inhibits it)
110
Q

types of double bonds in fatty acids

A
  • Exist as cis or trans isomers
  • Naturally occurring ones (made in body) are always cis
  • products can contain trans ones (these may be bad for you)
111
Q

fatty acid properties and storage

A
  • Fatty acids are insoluble in water
  • But they’re membrane permeant
  • Stored as esters with glycerol – TRIACYLGLYEROLS
112
Q

tricylglycerols

A
  • Main storage form of fat
  • 95% of fat in diet is triacylglycerol’s (as non-esterified fatty acids taste bad)
  • At temp. of body they’re liquid
  • Digestion begins in intestine
  • But in stomach they’re transferred into lipid droplets
113
Q

digestion of tricylglycerols

A
  • In stomach digested by pancreatic enzyme -> pancreatic lipase
  • the droplets have to be further broken down
  • Broken down by BILE SALTS
  • action of pancreatic lipase releases 2 fatty acids
  • Leaving one in the middle – that’s monoacylglycerol
  • both of these taken up by the intestine
114
Q

bile salts

A
  • Synthesised in liver
  • Stored in the gallbladder
  • Reach digestive tract through the bile duct
  • Detergents are amphipathic in structure (hydrophilic on outside and hydrophobic on inside)
115
Q

inhibitor of pancreatic lipase

A

orlistat

  • inhibits triacylglycerol breakdown
  • useful in treatment of weight
116
Q

digestion of tricylglycerol

A
  • by pancreatic lipase to fatty acids and monoacylglycerol
  • these are taken up by intestinal cells
  • 10% pass through portal system to liver
  • Majority of them are re-esterified to triacylglycerol and transported around the body as particles called chylomicrons
117
Q

chylomicrons contain

A
  • Triacylglycerides
  • Phospholipids
  • Proteins
  • Cholesterol
  • Fat-soluble vitamins – A, D, E, K

secreted from intestinal cells via lymphatic system

  • enter blood via thoracic duct
  • chylomicrons are a member of plasma lipoproteins
118
Q

chylomicrons general info

A

secreted from intestinal cells via lymphatic system

  • enter blood via thoracic duct
  • chylomicrons are a member of plasma lipoproteins
  • hydrophobic at centre
  • hydrophilic pn outside

circulate in the plasma

  • about 500nm in diameter
  • formed only in the intestine
  • rapidly broken down
  • half-life 5 mins
119
Q

degradation of chylomicrons

A
  • Picks up apoprotein C2
  • This activates the enzyme that degrades them -> LIPOPROTEIN LIPASE
  • This enzyme exposed on outside of endothelial cells
  • It hydrolyses the triacyclglycerols in chylomicrons all the way to free fatty acids and glycerol

Free fatty acids taken up by cells

  • Glycerol remains in plasma and taken up and metabolised by liver
  • Chylomicrons converted to remnants containing cholesterol and fat soluble vits.
  • Taken up by liver
120
Q

synthesis of fatty acids

A

First reaction catalysed by acetyl-CoA carboxylase

  • Important control point for synthesis and degradation
  • Acetyl CoA is carboxylated to malonyl-CoA
  • CO2 from bicarbonate
  • Require ATP
  • Intermediate is the enzyme with a bound CO2
  • Bound to prosthetic group Biotin (a vitamin)
121
Q

regulation of acetyl-CoA carboxylase

A
  • Exists in active and inactive forms
  • The inactive form is a phosphorylated form

activated by…

  • insulin
  • high blood glucose
  • high ATP production (so body can store molecules for later)

inactivated by…

  • glucagon
  • AMP-actiavted protein kinase (inc. AMP)
  • Long-chain fatty acyl-CoA
122
Q

fatty acid synthase pathway

A

1) Priming -> attaching acetyl group from acetyl-CoA to a cysteine sidechain (acyl-carrier protein) of fatty acid synthase

2) Loading -> transfer of a malonyl group from malonyl-CoA onto another sulfhydryl group (a vitamin prosthetic group on the enzyme)
- Enzyme now loaded with an acetyl group and a malonyl group attached as vio-ester

3) Next reaction is a condensation reaction
- Acetyl group transferred onto the malonyl group
- CO2 is lost which drives the equilibrium of the reaction
- Left with a 4 carbon oxo-acid attached to phosphopantetheine

4) Carbonyl group reduced in 2 steps (eliminating water)
- 1-> firstly to a hydroxy acid
- 2-> 4-carbon saturated fatty acid
- Reduction carried out by co-enzyme NADP (generated by pentose-phosphate pathways)

5) 4-carbon fatty acid elongated
- Transferred back to initial cysteine
- Enzyme reloaded with another malonyl-CoA
- Process repeated

123
Q

fatty acid synthase complex can convert acetyl CoA to…

A
  • Long-chain fatty acids which are saturated (even no.s of carbons)
  • End product is 16-carbon saturated fatty acid
  • Separate systems can elongate these further
124
Q

regulation of malonyl-CoA to fatty acids (from acetyl-CoA)

A

Insulin

  • Acetyl-CoA likely to come from glucose
  • uptake of glucose into fat and muscle controlled by insulin

Glucagon

  • inhibits glucose oxidation to pyruvate in the glycolytic pathway
  • (pyruvate enters mitochondria for oxidation to acetyl-CoA)

Malonyl-CoA

  • inhibits uptake of fatty-acyl CoA into mitochondria
  • so inhibits fatty acid oxidation
125
Q

de-saturation of fatty acids

A
  • Fatty acid synthase system makes saturated fatty acids
  • Formation of double bond involves the removal of 2 hydrogens
  • (These are used to reduce oxygen to water)
  • Other oxygen atom is reduced by reduced NAD
  • (So that desaturation requires enzymes, oxygen and reduced NAD)
126
Q

4 different desaturases - where do they insert bonds

A
  • Which introduce double bonds at carbons 4,5,6 or 9
  • Insertion of double bond starts at carbon 9
  • Other desaturases work closer to carboxyl groups
  • Introduction of double bonds past the carbon 9-10 junctions isn’t possible
  • This means some acids that we require which have double bonds at places other than 9 are ESSENTIAL
  • We can’t make them so they’re important in the diet
127
Q

examples of essential fatty acids

A

Linolenic which is a precursor for arachidonic acid
- which makes important molecules e.g. prostaglandins

omega-6 fatty acids

  • typically present in vegetable oils e.g. sunflower oil
  • recommended input is ~10 grams per day
  • big reservoir of fatty acid in the adipose tissue
  • so that if it fails in the diet
  • deficiency takes a while to develop
128
Q

mobilization of tricylglycerol

A
  • triacylglycerol stored in adipose tissue is hydrolysed by hormone sensitive lipase
  • pancreatic lipase in digestive system
  • lipoprotein lipase digests chylomicrons in the circulation
intracellular lipase 
activated by…
-	adrenalin
-	glucagon
-	growth hormone
inhibited by…
-	insulin
method…
-	takes one fatty acid of triacylglycerol
-	other lipases break it down further
- eventual product is glycerol + free fatty acids
129
Q

free fatty acids

A
  • Low solubility
  • Capable of diffusing through biological membrane
  • Doesn’t happen fast enough for rate of metabolism required
  • Transported bound to serum albumin
  • Total conc. Of free fatty acid rises to 0.6mmol/L during starvation
  • Very rapid turnover
  • Half-life is a few minutes
  • Enter cells with the aid of transporters
130
Q

fatty acid transport into cells - what do they attach to

A
  • Once they’re in cells to prevent leakage they’re attached to coenzyme A
  • Sequestered by protein called fatty-acid binding protein
  • Then co-enzyme A is attached in a process called fatty acid activation
  • (Requires ATP)
  • So fatty acids are taken up by cells and become acyl-CoA
  • (Long chain fatty acids esterified onto coenzyme A)
131
Q

cholesterol

A
  • 27 carbons
  • Many functions
  • Component of membranes
  • Precursor for bile acids and bile salts
  • Precursor of steroid hormones
  • Biosynthesis occurs in the liver mostly
  • Starts with acetyl CoA
132
Q

cholesterol synthesis regulated by

A

Level of HMG-CoA reductase

  • Biologically regulator of this is AMP-activated protein kinase
  • Phosphorylation inhibits this
  • No. of drugs used to inhibit HMG-CoA reductase
  • Statins
133
Q

intermediates in cholesterol synthesis

A 
acetyl-CoA
acetoacetyl-CoA
HMG-CoA
Mevalonate
Squalene
cholesterol
134
Q

production of bile acids

A
  • Cholesterol is hydrophobic
  • Bile salt Has to be made more hydrophilic to be used as a detergent

First step in this…

  • converted to 7 hydroxycholesterol by 7-alpha hydroxylase
  • Further hydroxylation’s and shortening of side chain
  • makes cholic acid and chenodeoxycholic acid (primary bile acids)

at this point they are hydrophilic on one side and hydrophobic on other side

  • then conjugated with glycine and taurine and go on to make secondary bile acids
135
Q

what are the 2 primary bile acids

A

Cholate and chenodeoxycholate

136
Q

what are the 2 amino acids that attach to the 2 primary bile acids

A

taurine and glycine

- this forms esters with the side chain = BILE SALTS

137
Q

the 4 primary bile salts info

A

4 bile salts formed by addition of sidechains to cholate and chenodeoxycholate

  • 2 corresponding to each
  • They are stored in the gall bladder
  • Bile salts enter digestive tract -> intestine

In intestine meet bacteria which modify bile salts

  • Hydrolyse to conjugated amino acids
  • Reduce them

2 more compounds formed -> LITHOCHOLATE & DEOXYCHOLATE
- Called secondary bile acids

138
Q

what does bile contain

A

bile salts

free cholesterol

139
Q

drugs used to lower plasma cholesterol

A

Cholestyramine

  • A resin which absorbs bile acids
  • Traps bile acids in the intestines
  • Can’t be reabsorbed and so is excreted

Plant sterols

  • Inhibit the uptake of cholesterol in the intestine
  • Eg benecol in synthetic margarine
  • Lower level of chol. In plasma

Statins

  • Inhibit de-novo cholesterol synthesis
  • Inhibit HMG-CoA reductase
  • But… when chol. Levels start to fall HMG-CoA reductase is upregulated
  • (body attempts to overcome statin)
  • Statin also upregulates receptors for LDL
  • So rate of uptake of cho. From plasma into tissues also inc.
  • Red. Of 30-60% in plasma chol. Levels

Fibrates

  • Lower triacylglycerol levels in the plasma
  • Effect cholesterol levels
  • Inc. rate of uptake of LDL into the liver
140
Q

transport of fatty acids into mitochondria by carnitine

A

Outer membrane of mitochondria isn’t a permeability barrier

  • Contains protein pores – porins
  • So acyl-CoA can easily enter space between the membranes
  • Cannot cross inner membrane
  • Its impermeable to
  • So acyl group transferred from acyl-CoA onto diff. molecule -> CARNITINE
  • Catalysed by enzyme on outer membrane -> CARNITINE PALMITOYL TRANSFERASE 1

Acyl- carnitine then imported through inner membrane in exchange for free carnitine
- Once inside acyl group transferred from carnitine back onto co-enzyme

141
Q

inhibition of transfer of acyl-CoA onto carnitine

A

This transport step is the rate limiting step in fatty acid oxidation

  • Transfer for acyl group catalysed by enzyme that’s inhibited by MALONYL-COA
  • Malonyl-CoA is synthesized by carboxylation of acetyl-CoA
  • Process under hormonal control
  • Malonyl-CoA is a precursor for fatty acid synthesis and inhibitor of fatty acid oxidation
142
Q

pyruvate dehydrogenase complex

A
  • it’s intra-mitochondrial (so pyruvate must enter mitochondria via a transporter)

Overall reaction of this enzyme is the oxidative decarboxylation of pyruvate

  • Oxidised to an acetyl group with loss of CO2
  • NAD is reduced to NADH
  • Acetyl group formed is esterified onto co-enzyme A
  • Making acetyl-CoA
143
Q

subunit prosthetic groups of pyruvate dehydrogenase

A

Pyruvate dehydrogenase subunit

  • Thiamine pyrophosphate (vit. B1)
  • Catalyses 1st step

Transacetylase
- Lipoic acid (a prosthetic group)

Dehydrogenase – which reoxidises the enzyme
- Flavin adenine dinucleotide (vit B2)

144
Q

thiamine deficiency

A

Thiamine deficiency occurs as a dietary deficiency called beri-beri, and wernickes neurological sympyomd

Also common in alcoholics as alcohol inhibits uptake of vitamin B1 and its processing into thiamine pyrophosphate
Symptoms include
- Tremor
- Paralysis

Alcoholism also induces hypoglycaemia crises

  • As it inhibits gluconeogenesis
  • If alcohol hypoglycaemia its nec. To check vit. B1 level
145
Q

pyruvate dehydrogenase regulation

A
  • By phosphorylation/dephosphorylation cycle
  • Dedicated kinase which phosphorylates it and thereby DEACTIVATES IT
  • Kinase activated by…
  • NADH
  • ATP
  • Acetyl-CoA
  • These are products of pyruvate oxidation
  • So pyruvate dehydrogenase products inhibits its activity (negative feedback)

Pyruvate dehydrogenase phosphatase

  • Takes phosphate off ACTIVATES the enzyme
  • Activated by…
  • Calcium
  • Insulin
  • So insulin stimulates pyruvate oxidation
146
Q

pyruvate pathway…

A
  • So pyruvate enters mitochondria and is oxidised to acetyl-CoA
  • Then incorporated into TCA cycle
  • A cyclic pathway in the matrix of the mitochondria

All enzymes in solution in mitochondria

  • Apart from succinate dehydrogenase
  • Bc it’s soluble in water
  • Part of inner mitochondrial membrane
147
Q

where/how does acetyl CoA enter the TCA cycle

A
  • by reaction with oxaloacetate to form citrate
148
Q

what are the 3 dehydrogenase which reduce NAD (to NADH) in the TCA cycle

A
  • Isocitrate dehydrogenase
  • Oxoglutarate dehydrogenase
  • Malate dehydrogenase
149
Q

what dehydrogenase reduces ubiquinone in the TCA cycle

A
  • succinate dehydrogenase

- ubiquinone is a co-enzyme (involed in fatty oxidation)

150
Q

how is GTP generated in the TCA cycle

A
  • Succinyl-CoA to succinate
  • Linked to GTP formation
  • This is called substrate level phosphorylation
151
Q

the oxidation of acetyl-CoA in the TCA cycle

A

Acetyl-CoA is completely oxidised as it goes around the cycle

  • 2 points at which CO2 is lost
  • > Isocitrate dehydrogenase
  • > Oxoglutarate dehydrogenase

So, acetyl-CoA (2 carbons) reacts with oxaloacetate (4 carbons) to form citrate
- Loses 2 carbons on the way round to return to oxaloacetate

152
Q

ketone body production

A
  • Produced in the liver
  • In times of starvation
  • When there’s considerable fat breakdown
  • Then acetyl-CoA formed by beta-oxidation builds up
  • Instead of being oxidised in the TCA cycle a lot of it’s diverted into ketone prod.
  • Takes part in mitochondria
  • First intermediate is HMG-CoA

Which is broken down into…

  • Acetoacetate
  • Reduced to 3-hydroxybutyrate
  • And acetone

These circulate in plasma
- Can be taken up by many tissues and oxidised as fuel (even by brain)

153
Q

acetoacetate circulation

A
  • Acetoacetate can be spontaneously decarboxylated
  • not an enzymic reaction (it’s just not vv stable)
  • product is acetone which isn’t further metabolized

acetone. ..
- it’s membrane permeant and volatile
- so when there are high conc. Of circulating ketones, you can smell acetone on the breath of the person
- this happens during starvation when conc. Of ketones rises to ~8 mmol/L in the plasma

  • or in type 1 diabetes when fat breakdown becomes unregulated and happens to great extent
  • conc. Of ketones can become vv high
  • 10,20,30, 50 mmol/L
  • Since they are strong acids they cause METABOLIC ACIDAEMIA
154
Q

mitochondrial ultrastructure

A

Infoldings of membrane to inc. surface area -> CHRISTAE

2 membranes
Outer membrane – permeable for proteins but not small molecules
- Has pores in it called porins
Inner membrane – more impermeable
- Carriers to transport molecules
- Electron transport chain components are integral membrane proteins to it

Space between membranes -> MITOCHONDRIAL MATRIX

  • Certain proteins in here
  • All oxidative enzyme of TCA cycle are inside this space
155
Q

electron transport chain

A
  • A series of carriers that are able to pass electrons from one to another

Carrier A
- Becomes reduced by accepting electrons from an electron donor
Reduced form of A reduces oxidised form of next form -> carrier B
Then reduced form of B reoxidised by transfer of electrons to the final electron acceptor

Movement of electrons from carriers of lower affinity for electrons to carriers with higher affinity for electrons

  • This is called redox potential
  • So carriers on left have lower redox potential than those on the right
156
Q

prosthetic groups in the electron transport chain

A
  • These are prosthetic groups
  • Attached to proteins either
  • Covalently
  • Or by strong non-covalent bonds

1) Flavoproteins
- Have a flavin prosthetic group
- Flavin derived from vitamin B2 (or riboflavin)
- 2 forms of prosthetic group…
- Flavin mononucleotide (FMN)
- Flavin adenine dinucleotide (FAD)
- Flavin can accept 2 hydrogens and become reduced
- Ie it’s a hydrogen carrier

2) Iron-sulfur clusters
- Prosthetic group is formed by a cluster of iron and sulphur atoms
- And side chains of cysteines in the protein
- Can accept electrons
- Acts as a single-electron carrier
- One iron goes from the ferric to the ferrous form

157
Q

ubiquinone

A
  • A co-enzyme
  • Free in mitochondrial inner membrane
  • part of the electron transport chain

Not derived from vitamin

  • It’s synthesised
  • The pathway that synthesises it starts of as the same pathway that synthesises cholesterol
  • Maybe why statin drugs can have effects on muscle activity?

It’s very hydrophobic

  • Dissolved in the inner mitochondrial membrane
  • Acts as a hydrogen carrier
158
Q

cytochrome C

A
  • Have an iron atom co-ordinated by a series of 4 5-membered ring
  • Called HAEM
  • Diff. types of haem depending on sidechains of the rings
  • They may be covalently or non-covalently attached to proteins
    Cytochrome C
  • Simplest and smallest cytochrome in mitochondria
  • Has haem covalently attached to cysteine side chains
  • Molecular weight about 12,000
  • transfers electrons from carrier III to IV in electron transport chain

Haems act as electron carriers because the iron can exist in ferrous or ferric forms
- Ferric form accepts electron and becomes ferrous

159
Q

inhibitors of mitochondrial complexes

A

Rotenone

  • Plant-derived poison
  • Used as an insecticide/ fish poison
  • Inhibits complex 1 by binding to it and blocking the elctron transport chain

Atovaquone

  • Inhibits complex 2
  • Component of anti-malaria drug malatone

Cyanide and CO

  • Inhibit complex 4
  • Block electron transport to oxygen
  • Vv toxic
160
Q

how is ATP made

A
  • Made by complex 5 -> ATP synthase
  • Doesn’t have a redox prosthetic group
  • Works through a proton circuit in the mitochondrial membrane
  • Electron transport chain translocate proteins out of the mitochondrial matrix
  • Setting up an electro-chemical gradient of protons

This has 2 components…

  • A small diff. in pH ~1.5 units
  • pH inside mitochondria is higher than outside
  • as proton conc. Inside is reduced
  • there is a membrane potential of ~150 millivolts
  • arises bc/ protons are pos. charged
  • so electron transport along the chain translocate out these protons
  • setting up an electrochemical gradient of protons
  • used as of energy for ATP synthesis
  • bc protons return through ATP SYNTHASE which drives synthesis of ATP
161
Q

proton circuit through mitochondria

A

Electron transport chain in the inner membrane

  • Oxidizing reduced NAD
  • Reducing oxygen to water
  • Blockable via
  • Rotenone, antimycin, cyanide
  • Electron transport translocates protons out of mitochondrial matrix
  • And in the circuit, they then return through ATP Synthase
  • Inhibited by oligomycin

Drives synthesis of ADP + Pi to ATP

162
Q

when can ATP synthesis go wrong

A
  • Depends upon inner membrane being completely impermeable to protons
  • If impermeability breaks down then protons short-circuit
  • Protons are pumped out and they come back in without the ATP being made
  • Energy then released as heat
  • Occurs if there’s mitochondrial damage
163
Q

unicouplers

A
  • Eg 2, 4 dinitrophenol used as explosives in WWII
  • Lipid-soluble weak acids
  • Bind protons on the outside, diffuse through membrane, release them inside
  • Energy from oxidation is not conserved as ATP – instead released as heat

also occurs in brown fat of hibernating animals

164
Q

yield of ATP from the proton circuit

A

P/O ratio = number of molecules of ATP produced per atom of oxygen reduced
- E.g. Mol. Of ATP per 2 electrons moving along the chain
In terms of proton circuit theory -> CHEMIOSMOTIC THEORY
- No. of protons from reducing an oxygen divided by number of protons you need to make an ATP

  • For oxidation of NADH by oxygen 10 protons translocated
  • ATP synthase makes 3 ATPs from translocation of 8 protons
  • So number of protons per ATP ~8/3 -> ~3
  • Take into account the proton required for phosphate import
165
Q

yield of ATP for NADH oxidation

A
  • 10 protons come out
  • ~4 protons are needed to make an ATP
  • So P/O ratio is about 2.5 (3)
166
Q

yield of ATP for succinate oxidation

A
  • No. of protons translocated is 6 (from reoxidation of ubiquinone)
  • So P/O ratio is 6/(3 + 1)
  • About 1.5 (2)
167
Q

differences in metabolism in stavation vs trauma

A

basal metabolic rate inc. during trauma but dec. during starvation

nitrogen balance dec. during trauma but inc. during starvation

year 2 sem 1 (13 decks)

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