Metabolism Flashcards
1
Q
Name the 3 non carbohydrate precursors of glucose :
A
1 lactate
2 amino acids (alanine in skeletal muscle)
3 glycerol (triacylglycerols in fat tissue )
2
Q
Which organs are involved in gluconeogenesis :
A
Liver (90%), kidney and small intestine
3
Q
Where in the cells does gluconeogenesis occur?
A
Cytosol (except for the first reaction )
Most of the same glycolysis enzymes involved
4
Q
Summarise how gluconeogenesis occurs:
A
Reversal of glycolysis except for 3 steps
- Pyruvate converted to PEP
- F1,6BP converted to F6P
- G6P converted to glucose
5
Q
Explain the importance of pyruvate carboxylate
A
Catalyses an important anapleurotic reaction
This means it maintains the conc of Krebs cycle intermediates, allowing it to be a continuous process
6
Q
Name the reactions involved in gluconeogenesis and the enzymes involved
A
7
Q
How do the 3 glucose precursors join the gluconeogenesis pathway ?
A
Lactate —> pyruvate
Lactate DH
Amino acids —> oxaloacetate + pyruvate
Transamination
Glycerol —>dihydroxyacetone phosphate —>glyceraldehyde 3-phosphate
8
Q
State the 2 condition for gluconeogenesis
A
Low [glucose] and high [ATP]
9
Q
glycolysis and gluconeogenesis can occur simultaneously
true or false
A
False
when one pathway is active, the other must be inactive
10
Q
What conditions inhibit Gluconeogenesis
A
High AMP/F1,6P/ADP
11
Q
What conditions stimulate gluconeogenesis
A
High acetyl CoA / citrate
12
Q
What conditions inhibit glycolysis
A
High ATP/Citrate/H+/alanine
13
Q
What conditions stimulate glycolysis
A
High F2,6P as this stimulate PFK-1 involved in the irreversible step; high AMP (as this indicate there is low ATP); insulin secretion
14
Q
Describe the effects of insulin
A
Promote synthesis of glycolysis enzymes e.g. PFK/PK/PFK2
Inhibit synthesis of PEPCK ; this inhibits gluconeogenesis
15
Q
Describe the effects of glucagon
A
Increases expression of PEPCK/F1,6BPase
increased gluconeogenesis
16
Q
Draw the Krebs cycle
A
citrate is krebs special substrate for making oxaloacetate.
17
Q
What is the PDH reaction
A
the link reaction
converts pyruvate to acetyl CoA
18
Q
Name the4 5 coenzymes of PDH
A
Thiamine pyrophosphate (TPP)
Lipoamide
CoA
FAD+
NAD+
19
Q
draw the mechanism of the PDH reaction
A
20
Q
Name the 3 enzymes found within the PDH complex
A
E1 pyruvate decarboxylase
E2 hydrolipoyl transacetylase
E3 dihydrolipoyl dehydrogenase
21
Q
What conditions cause activation of PDH
A
Increased [insulin] and [Ca2+]
this cause dephosphorylation of PDH
22
Q
What conditions cause the inhibition of PDH
A
Increased ATP/NADH/Acetyl CoA
results in phosphorylation of PDH via kinase
23
Q
Name the 3 enzymes needed for glycogen formation
A
Glycogenin
glycogen synthase
branching enzyme
24
Q
State the role of glycogenin
A
Combine UDP-glucose (activated form of glucose) to tyrosine
25
describe the role of glycogen synthase
Make alpha 1,4 glycosidic bond cause the chain to extend
26
describe the role of the branching enzyme
Breaks off part of the amylose chain and branches it via the formation of alpha 1,6 glycosidic bonds
27
When does glycogenesis occur in the liver and skeletal muscle
In the liver - during well fed periods
in skeletal muscle : during rest periods
28
Describe the hormonal regulation of glycogenolysis
Glucagon bind to receptors on hepatocytes / adrenaline binds to myocyte/hepatocytes
adenylyl cyclase activated by G proteins ; makes cAMP
cAMP activates protein kinase A ; phosphorylates glycogen
inhibition of glycogen synthesis
29
Characteristics of high energy state
30
Characteristics of low energy state
31
Breakdown of adipose tissue forms:
Triacylglycerol which is converted to free fatty acid (FFA) and glycerol
glycerol acts as a gluceneogenic substrate
FFA form acetyl CoA
32
describe the structure of triacylglycerol
glycerol backbone with 3 fatty acid chains attached
the fatty acid chains may be saturated or unsaturated
33
Describe the mobilisation of fatty acids
In response to glucagon or adrenaline , hormone-sensitive lipase hydrolyses triacylglycerol in adipose tissue to free fatty acids and glycerol
34
How are fatty acids transported to the skeletal muscle from adipose tissue?
Free fatty acids(FFA) bind to albumin in blood and travel via circulation to muscle
35
Describe mitochondrial beta oxidation of fatty acids
Long Chain fatty acids (LCFA) activated in cytosol to form fatty acyl CoA
these are then transported to mito where beta oxidation in matrix occurs to form NADH, FADH2 and acetyl CoA
2C removed from fatty acids in each round ; this continues until the LCFAs are fully broken down
36
State the energy yield starting with a C16 saturated fatty acid (typical fatty acid)
7FADH2 = 14 ATP (beta-oxidation occurs 7 times)
7NADH = 21 ATP
8 acetyl CoA = 96 ATP via the TCA cycle
Net yield of 129 ATP (2 needed to form LC fatty acylCoA)
37
Describe the pathway of fatty acid synthesis
Acetyl CoA (2C-CoA) ⇒ malonyl CoA (3C-CoA) ⇒ 16C-CoA ⇒TAG
38
state the two functions of acetyl CoA
Fed into TCA cycle
form ketone bodies
39
What are Ketone bodies
Alternate fuel for cells during starvation/uncontrolled diabetes ; especially important for brain
made from acetyl CoA in liver mitochondria
occur when high [AcCoA]
40
Name the ketone bodies
Acetoacetate ⇒ beta-hydroxybutyrate + acetone
41
Utilisation of ketone bodies
preferentially metabolised in brain/heart during starvation to preserve glucose for use elsewhere
42
Ketoacidosis - what is this
when [ketone body] is too high , ketones are secreted in urine (ketonuria)
ketone bodies are acidic so lower blood pH which can be life threatening
43
what is cholesterol
essential molecule
component of cell membrane
precursor to bile acids, steroid hormones and vitamin D
44
Biosynthesis of cholesterol
45
what is the purpose of lipoproteins
Allow transport of lipids around the body
46
Structure of lipoproteins
Globular shape
outer layer of unesterified cholesterol and phospholipid
inside cholesteryl ester and TAG
apoprotein wrapped around the outside
47
Function of apoproteins
Interact with cellular receptors
activate and inhibit enzymes involved in lipoprotein metabolism
48
Function of chylomicrons
Secreted into lymph and reach blood plasma via thoracic duct
they are then transported to adipose tissue or muscle where they are converted to FFA so they can cross the capillary endothelium
the FFA are then converted back into TG once inside the adipose/muscle tissue
49
describe the intestinal uptake of dietary lipids
Triacylglycerides broken down fatty acids + monocyglycerols just outside cell then recombined once they enter the cell
triacylglycerides are combined with other lipids and proteins to form chylomicrons which are transported to circulatory system via the lymph system
50
What is the importance of the apoprotein CII
Activates lipoprotein lipase (LPL)
LPL catalyses the reaction TG⇒FFA + glycerol
LPL found on surface of endothelial cells
this means FFA are liberated when chylomicrons reach their end destination in the blood
51
What are chylomicron remnants ?
what is their function ?
They are also formed when the CM are converted to FFA to allow exit from the plasm a
CM remnant deliver dietary cholesterol to the liver
52
What are endogenous lipids ?
Formed when there is excess carbohydrate and lipids in diet
excess carbs/lipids ⇒ TAG (in liver)
53
What are endogenous lipids ?
Formed when there is excess carbohydrate and lipids in diet
excess carbs/lipids ⇒ TAG (in liver)
54
What is VLDL
Transports endogenous TAGs to peripheral tissues
55
What are IDLs
Intermediate density lipoprotein
formed by removal of triacylglycerol from VLDL
they can either be sent to the liver and be destroyed or lose more triacylglycerol and become LDL such as cholesterol
56
What is LDL
Formed via the removal of TG from IDL
contains apoB-100, esterified cholesterol and normal cholesterol
major cholesterol carrier to tissues
high levels of LDL associated with CHD
57
Compare metabolism of dietary lipid vs endogenous lipids
Digestive lipids absorbed in liver; endogenous in liver
digestive lipids converted to CMs; endogenous to VLDL
both VLDL and CM catalysed by LPL to release FFA
VLDL broken down to form FFA and IDL ; CM broken down to form FFA and CM remnants
CM remnants go to liver ; IDL can either be converted to LDL or be destroyed in liver
58
What is HDL
Transports cholesterol from peripheral tissue to liver ; this is called reverse cholesterol transport
it helps protect against CHD
59
Define anabolism
Synthesise large molecules
60
What are the 4 types of metabolic pathways
fuel oxidative pathways (breakdown substrates)
fuel storage and mobilisation
bio synthetic pathways
detoxification and waste disposal pathways
61
What is catabolism
Breakdown on large molecules
62
What is metabolic homeostasis
Control of the balance between substrate availability and need caused by anabolic and catabolic pathways
63
Glucagon :
Where does it act
where is it made?
describe its effects
Made by alpha cells in islets of lagerhans in pancreas
Glucagon acts to maintain fuel availability
principally acts in liver and adipose tissue not in muscle however
Promotes glycogenolysis and gluconeogenesis/ketogenesis
mobilises fatty acids from adipose triacylglycerols
reduces glycogen synthesis in liver
increasses [adrenaline]
64
how is insulin made?
Describe the action of insulin
Polypeptide synthesised as a preprohormone
degraded by liver, kidney and skeletal muscle where its converted to its final form
Acts on liver, muscle and adipose tissue
65
How is glucagon made
Produces as preprohormone in RER
degraded by liver and kidneys
66
What promotes glucagon release?
release of catceholamines (such as adrenaline)
high amino acid conc
low blood glucose
67
Describe the 2 types of signal transduction
Receptor coupled to adenylate cyclise to produce cAMP
receptor/kinase activity
receptor couples to hydrolysis of PIP2
68
intracellular effects of insulin
overall has an anabolic effect
effect on carb metabolism:
* stimulates uptake of glucose from blood
* incorporation of vesicles with GLUT4 receptors into membrane
* stimulates storage of glucose in liver primarily
* phosphorylation of glucose/PFK/glycogen synthase = increased glycogen synthesis
* cells driven to preferentially oxidise carbs over fatty acids/AA
effect on lipid metabolism:
* promotes synthesis of FAs in liver from excess glucose which are then used to make lipoproteins which travel in blood
* promotes accumulation of TGs in adipose tissue by inhibiting hydrolysis of TGs
effect on protein metabolism
* increased uptake of amino acids/ protein synthesis
69
intracellular events of glucagon
Secondary messenger activation
glucagon binds to G-protein coupled receptor
G protein dissociates = cAMP formed = protein kinase activated
protein kinase phosphorylase’s regulatory enzymes in order to control lipid/carb metabolism
70
Complete this table
71
what is the fed state ?
Period of 2-4 hrs after a meal
characterised by an anabolic state : increased TAG and glycogen synthesis
72
How is the liver adapted for metabolism
Blood containing nutrients and hormones from gut and pancreas directly passes through liver before returning to heart
the liver absorbs the carbs/lipids/aa to be broken down, stored or redistributed
73
Excess glucose is converted to ….
TAG which is then packages into very low density lipoproteins (VLDL)
74
What happens after carb intake occurs
Increased glucose uptake by hepatocytes ; insulin independent glucose transporters (GLUT-2) have high Km
increased phosphorylation of glucose
excess glucose to form TAG
increased glycogenesis
increased activity of the pentose phosphate pathway/hexose monophosphate (uses up to 10% of glucose)
75
When does glycolysis mainly occur ?
Glycolysis mainly occurs during the absorptive period after a carb rich meal
76
Where is the primary site of fatty acid synthesis
The liver
77
Describe the degradation of amino acids
Deamination of amino acids to form urea
carbon skeleton will be degraded to pyruvate, acetyl CoA, or TCA cycle intermediates
78
What is the function of the pentose phosphate pathway
Produce NADPH which is needed for fat synthesis
79
what occurs in the skeletal muscle during the fed state
Glucose used to replenish glycogen stores depleted by exercise
increased uptake of BCAAs
increased insulin:glucagon
FAs are of secondary importance to glucose during resting stage
80
Describe the fuel used by the brain tissue
No significant glycogen/TAG stores as they cannot cross the blood-Brian barrier
blood glucose is the fuel used and sometimes ketone bodies
81
Describe the symptoms refeeding syndrome
after prolonged starvation, a meal can bring complications
symptoms:
most commonly hypophosphataemia
hypokalaemia(cuases arrhythmias and cardiac arrest) and hypomagnesaemia (cardiac dysfunction)
can be fatal
82
what kind of people at risk of refeeding syndrome
malnourished due to anorexia nervosa, dysphagia, alcoholism, depression, old age, uncontrolled diabetes
reduced ability to absorb due to bowel disorders such as IBS, coeliac disease, CF
increased metabolic demands due to cancer or surgery
83
What happens during refeeding syndrome
During starved state, ketones and FAs become major fuel source
during prolonged starvation, intracellular minerals become depleted (These are needed as cofactors); with the aim to preserve muscle breakdown, decreased use of FA and ketones, brain switches to ketones
during refeeding, shift back to carb metabolism ;
insulin stimulates macromolecule synthesis which requires minerals
uptake of minerals by cell from blood leads to osmotic issues in cells and lack of PO42-, K+ and Mg2+ in blood
84
Breakdown of carbohydrates
digested by alpha-amylase and disaccharidases
glucose is oxidised for energy
glucose forms the carbon skeleton of most compounds
85
Protein breakdown
cleaved by pepsin in stomach and proteolytic enzymes in pancreas
proteins used for neurotransmitter and heme synthesis
carbon skeleton may be oxidised
86
How does glucose enter b-cells?
GLUT-2 transporter = facilitated diffusion phosphorylated by glucokinase glucose-6-phosphate metabolised via glycolysis
87
what happens after glucose enters Beta cells in islets of langerhans ?
ATP levels rise rise in ATP = potassium pump starts working, leaves cell, voltage potential changes, calcium diffuses in, signalling molecules are told to release insulin
88
How does the liver aid in metabolism?
connection between digestive tract and circulatory system
venous drainage of gut and pancreas passes through the hepatic portal vein
liver takes up carbohydrates, lipids and amino acids from blood
89
describe carb metabolism during the fed state [7]
Increased glucose uptake by hepatocytes (GLUT2),
increased phosphorylation of glucose (glucokinase creates G6P),
Excess glucose is converted to TAG (packaged in VLDL),
increased glycogenesis (glycogen synthase activated),
increased activity of pentose phosphate pathway,
increased insulin-to-glucagon results in increased
glycolytic enzymes (glucokinase, PFK1, pyruvate kinase), decreased production of glucose
90
Import of LCFAs into mitochondria
CoA esters cannot cross mitochondrial inner membrane,
long chain fatty acyl group transferred to carnitine,
LCF acyl carnitine transported into mitochondrial matrix (carnitin exported),
LCF acyl group transferred to CoA
* * *
91
how do short and medium fatty acids get converted to fatty acylCoAs?
short and medium chain fatty acids pass directly into mitochondria where they are activated to fatty acylCoAs
92
describe carbohydrate metabolism (starved state)
Liver: Glycogen degradation occurs first, followed by gluconeogenesis. Also produces ketone bodies.
The carbon skeletons from gluconeogenesis are derived from glucogenic aa, lactate from muscle and glycerol from adipose tissue.
93
reaction 1 of glycolysis
Irreversible.
Phosphorylation: -traps glucose inside the cell;
-ive charge at physiological pH.
conserves metabolic energy.
phosphates interact with enzyme active sites and lower activation energy.
Catalysed by GLUCOKINASE in the liver or HEXOKINASE in muscle/fat.
94
describe reaction 3 of glycolysis
what are the enzymes involved
what type of reaction is it
the phosphorylation of fructose 6-phosPhate
irreversible reaction,
rate limiting,
catalysed by phosphofructokinase-1.
Most important control point
Inhibited by high ATP and citrate
95
how are glycogenolysis and calcium linked
calcium is released into cytoplasm after neutral stimulation, released from sarcoplasmic reticulum
this leads to glycogenolysis in the muscle
96
what is the importance of glycerol ?
transported to liver, phosphorylated to glycerol-3-phosphate and converted to DHAP: used in glycolysis or gluconeogenesis
97
gluconeogenesis ;
when does it occur and which substrate is used
Exercise: lactate Sort term fasting: alanine Diabetes: insulin sensitivity Trauma: peripheral insulin resistance
98
how is metabolic flux controlled?
by controlling enzymes involved, hence inhibiting or stimulating different reactions
99
when does the starved state occur?
\>3 days after last meal
100
Describe the fuel use of muscle
Glucose, fatty acids and ketone bodies
glycogen store can be converted to glucose for contraction (glucose prioritised for contraction)
FAs are primarily used by resting muscle
101
Describe the fuel use of the heart
Fatty acids
ketone bodies
lactate
no glycogen reserves
102
Describe the fuel use of adipose tissue
Needs glycerol 3-phosphate to creat triacylglycerols
needs glucose for glycolytic intermediate dihydroxyacetone phosphate (then it is reduced to G-3-P)
103
Metabolic functions of liver
makes fuel for brain, muscle and peripheral organs
metabolises ⅔ of glucose to form glycogen
turns fatty acids to ketone bodies
uses alpha-keto acids from amino acids
104
Describe what occurs in the liver during the starved state
in liver:
* glycogenolysis first then gluconeogenesis
* increased glucagon:insulin
* Carbon skeletons of glucose derived from glucogenic amino acids, lactate from muscle and glycerol from adipose
* ketone body production (conc drops during prolonged starvation due to organ shutdown)
* NADH produced inhibits TCA cycle
* Acetyl CoA produced activates pyruvate carboxylase and inhibits pyruvate dehydrogenase
* Fatty acid Oxidation is the major energy source
105
What occurs in adipose tissue during the starved state
TAG lipolysis = releases FAs
decreased uptake of fatty acids and glucose so reduced glycolysis/TAG synthesis
106
role of kidney in fasting state
In late fasting 50% of gluconeogenesis occurs here
uses self generated glucose
compensates for acidosis caused by ketone bodies
107
Summary of starved state
at first brain uses glucose
beyond 2-3 weeks ketone bodies replace glucose usage
as glucose no longer required, protein catabolism for gluconeogenesis not needed either - lower protein degradation
kidney becomes more important : most gluconeogenesis occurs here now to provide kidneys with glucose to counteract acidosis from ketone bodies
108
Diabetes mellitus
type 1
describe and explain the symptoms
early onset - childhood or adolescence; hyperglycaemia causes increased urination/thirst/weight loss/ increased appetite; diabetic ketoacidosis = persistent fatigue, dry or flushed skin, abdominal pain, nausea or vomiting, confusion, trouble breathing, and a fruity breath odor
108
Diabetes mellitus
type 1
describe and explain the pathophysiology
caused by autoimmune attack on beta cells in islets of langerhans
hyperglycaemia and ketoacidosis :
* increased gluconeogenesis
* increased mobilisation/oxidation of FAs
* leads to increased 3-hydroxybutyrate and acetoactetate
Hypertriacylglycerolemia:
* excess FAs are converted to TAG
* low lipoprotein degradation by LPL
* reduced enzyme production
* excess chylomicrons and VLDL
109
Type II diabetes
explain the pathophysiology
Caused by a combination of insulin resistance and dysfunctional beta cells
hyperglycaemia
* increased hepatic production and reduced peripheral use
* ketosis is minimal as insulin is usually present in small amounts
dislipidemia
* FAs converted to TAG and secreted as VLDL (can cause plaques)
* chylomicrons synthesised from dietary lipids in intestine
* but LPL is low so VLDL/chylomicrons are elevated
110
Describe how ATP is formed from NADH and FADH2
TCA cycle produces 1 FADH2 and 3NADH molecules (8 e- in total)
NADH binds to complex I and it transfers its e- to CoQ ; 4 H+ pumped from matrix to IMS
complex II accepts e- from FADH2 and transfers them to CoQ
CoQ transfer all these e- to complex III ; e- accepting by heme group within ; the e- are then given to cytochrome c ; 2 H+ also pumped
cytochrome c transfer the e- to complex IV ; e- transferred to oxygen to form water ; 8 protons pumped across
111
Describe the ETC
Found on inner mitochondrial membrane
4 protein complexes :
3 proton pumps(complexes I,III and IV) and 1 linking to the TCA cycle (complex II)
2 small components:
CoQ and cytochrome C - they are free to move inbetween membranes
H+ return to matrix via ATP synthase; coupled with ATP synthesis
NADH makes 3 ATP
FADH2 makes 2 ATP
112
Name 3 examples of ETC inhibitors
cyanide
azide
CO
(all these inhibit complex IV)
113
Name 3 examples of ETC uncouplers
Dinitrophenol (synthetic)
thermogenin (natural)
114
what would high lactate DH in blood indicate?
lots of anaerobic resp so there must be a lack of oxygen ; MI/ischaemia/necrotic bowel
