Biochemistry Flashcards
Define glycogenesis
Synthesis of glycogen from glucose
Define glycogenolysis
Breakdown of glycogen to form glucose
Define gluconeogenesis
De novo synthesis of glucose from metabolic precursors (lactate, amino acids, glycerol)
What is glycogen?
Main storage form of glucose in liver and muscle cells
Describe liver glycogen
Broken down between meals and released to maintain blood glucose levels for red blood cells and brain. Glucose homeostasis
Describe muscle glycogen
Not available for maintenance of blood glucose levels. Provides energy via glycolysis and the TCA during bursts of physical activity
Which process fluctuates dependent upon meal times?
Glycogenolysis
What is the primary source of glucose overnight when hepatic glycogen is depleted?
Gluconeogenesis
Describe the structure of glycogen
- glycogen is a polymer consisting of glucose molecules
- joined by an alpha 1-4 glycosidic links
- branches are introduced by alpha 1-6 glycosidic links
Glucose residues can only be added to where?
An existing glycogen chain. A glycogen ‘primer’ containing at least 4 glucose residues is required . The primer is covalently attached to a protein called glycogenin
Name the first enzyme in glycolysis
Hexokinase
What is the role of phosphoglucomutase?
Repositions phosphate 6 to position 1, this is a liver specific reaction. G1P is now primed for glycogen synthesis
Describe UDP-glucose
- simple precursors are first converted to activated intermediates, a common feature of biosynthetic pathways
- UDP-glucose can be though of as an ‘activated’ form of glucose
- ATP and acetyl-CoA are activated forms of phosphate and acetate, respectively
- the phosphate ester linkage in a nucleotide sugar releases free energy on hydrolysis
Describe glycogen synthase
- synthesis glycogen from UDP-glucose
- adds one glucose molecule to glycogen at a time
- can only extend the chains of glycogen, cannot start new molecules
- can not introduce branches
- rate limiting enzyme of glycogenesis
Describe transglycosylase
- branching enzyme
- introduces an alpha 1-6 glycosidic branch into glycogen
- approx. every 10 glycogen residues
What is the rate limiting enzyme of glycogenesis ?
Glycogen synthase
What catalyses glycogenolysis?
Glycogen phosphorylase
Describe the rate limiting step of glycogenolysis
- catalysed by glycogen phosphorylase
- one glucose molecule is cleaved off the ends of glycogen at a time
- glucose 1 phosphate is then converted to glucose 6 phosphate
- end point is release of free glucose into the bloodstream
Describe glycogenolysis in the liver
Glucose 6 phosphate can be de-phosphorylated and the resulting glucose released into the bloodstream via GLUT 2 transporter
Describe glycogenolysis in skeletal muscle
Glucose 6 phosphate cannot be de-phosphorylated but instead is used to provide energy via glycolysis and the TCA cycle
Describe the precursors of gluconeogenesis
- lactate; synthesised by skeletal muscle under anaerobic conditions
- amino acids; derived from muscle protein by proteolysis
- glycerol; derived from triglycerides by lipolysis in adipose tissue
Describe the energy source for gluconeogenesis
From oxidation of fatty acids released from adipose tissue
Describe the location of gluconeogenesis
Mainly in the liver, small amounts in the kidneys
Why is gluconeogenesis NOT the reverse of glycolysis?
There are irreversible steps
What are the three unique liver enzymes required for gluconeogenesis?
- glucose 6 phosphatase
- fructose 1,6 biphosphotase
- PEP carboxykinase
Which enzyme allows for the bypassing of pyruvate kinase?
PEP carboxykinase
Which enzyme allows for the bypass of fructose?
Fructose 1,6 biphosphate
Which enzyme dephosphorylates glucose 6P to form glucose?
Glucose 6 phosphatase
Describe the cori cycle
- lactate as a precursor of gluconeogenesis; formed in fast-twitch muscle under conditions of heavy exercise
- blood transports lactate to liver
- glucose released into bloodstream
- buys time and shifts metabolic burden from muscle to other organs
- the process of removing lactate that is generated in the skeletal muscle, to convert it back to glucose through the gluconeogenic pathway therefore to maintain blood sugar homeostasis
Amino acids can act as precursors for what?
Gluconeogenesis
Describe glycogen storage disease
- group of disease with increased glycogen deposits in liver or muscle or both
- at least 10 different types, each one due to a defect in a different enzyme
Increased fat intake without appropriate energy expenditure leads to what?
- increase in numbers of adipocytes
- more fat in adipocytes
- obesity
Control of energy balance depends on what?
- genetically linked factors; eg protein messengers regulating appetite
- environmental factors; eg, food abundance, fashionable foods
Uncoupling generates what?
Heat
Why is fat required for essential fatty acids?
- some polyunsaturated fatty acids can not be made by the body
- deficiencies can lead to membrane disorders, increased skin permeability, mitochondrial damage
Why is fat required for fat-soluble vitamins?
- vitamins A,D,E and K
- absorption of these vitamins is closely linked to that of fat
- stored in body fat
What can occur if fat intake or absorption is inadequate?
Secondary deficiencies can occur
What are the three different types of lipids?
- simple lipids (fatty acids, triglycerides, waxes)
- compound lipids (phospho, glycol-lipids, lipoproteins)
- steroids (cholesterol, steroid hormones)
Describe lipids
- predominantly hydrocarbon
- usually contain long chain fatty acids
- insoluble in water
- important for their biological function
Describe triglycerides
- triacylglycerols
- main energy storage for in adipose tissue
- compact; don’t require concomitant storage of water
- hydrophobic
- high energy yield per gram
Describe the structure of triglycerides
Consists of glycerol and 3 fatty acids
Describe fatty acids
- mainly straight chains
- aliphatic (no rings)
- usually contain an even number of C atoms
- branched chain and odd numbers of C are rare
- can be saturated (no double bonds)
- unsaturated (one double bond)
- polyunsaturated (several double bonds)
- double bonds usually in cis configuration
Name the three main natural fatty acids
- palmitic acid
- stearic acid
- oleic acid
Describe polyunsaturated fatty acids
- occur only in small amounts
- many can not be synthesised by the body
- essential fatty acids
- eg. linoleic acid
Which carbon is the alpha carbon in fatty acids?
The C adjacent to the carboxyl group
Which carbon is the omega carbon in fatty acids?
The terminal carbon
Describe the structure of omega 3
There is a double bond three positions up from the terminal omega carbon
Fatty acids with up to 8C atoms are what at room temperature?
Liquids
Plant fats contain what?
Large proportions of unsaturated fatty acids»_space; liquid
Animal fats contain what?
Mostly palmitic and stearic acid»_space; solid
Name the main products of fat digestion
- glycerol
- fatty acids
- monoglycerides
What is absorbed into mucosal cells of the intestine?
- short and medium length fatty acids enter portal blood
- longer chain FAs and monoglycerides are re-synthesised to triglycerides
Describe chylomicrons
Coated with a layer of protein, phospholipid and cholesterol. Carrier of polar components that arises from the digestion of lipids. Enter lymph, then the blood stream
At muscle and adipose tissue, chylomicrons are attacked and cleaved by what?
Lipoprotein lipases
Once chylomicrons are cleaved by lipoprotein lipases. free fatty acids are what?
- resynthesised into triaclyglycerols (in adipose tissue for storage)
- oxidised to provide energy (in muscle)
- depends on amount available
What is lipolysis?
Breakdown of lipids
Where is fat stored?
In adipose tissue
Initial cleavage is by what molecule?
- hormone sensitive lipases (eg. adrenaline sensitive)
- releases free fatty acids and glycerol
- occurs when energy is needed
What do hormone sensitive lipases do?
Break the lipids down into constituent parts
Describe fatty acid oxidation
- before fatty acids can be oxidised to generate energy, they have to be converted to CoA derivatives
- occurs in cytoplasm
- requires energy (equivalent of 2 ATP)
- further oxidation of fatty acids occurs in mitochondrial matrix so need to be transported into mitochondria by special carrier mechanism
Describe the carnitine shuttle
- in the cytoplasm, fatty acids are transferred from acyl- CoA to carnitine
- acyl-carnitine transporter in inner membrane facilitates antiport of acyl-carnitine into the mitochondrion and carnitine out
- net result; acyl-CoA located in mitochondrial matrix
Name the rate limiting step of energy conversion from fatty acids to ATP
The carnitine shuttle
Rate limiting of lipids crossing the cytoplasm into mitochondrial matrix
What is beta oxidation?
- cycle of reactions in mitochondrial matrix
- four steps in each cycle
Name the rate limiting molecule of beta oxidation
Acetyl CoA
Name the end products for each cycle of beta oxidation
- 1 acetyl-CoA
- 1 FADH2
- 1 NADH and H+
- 1 fatty acyl-CoA, shortened by 2 carbon atoms
The TCA cycle is initiated by which molecule?
Acetyl CoA
What is the final yield of beta oxidation?
- 8 FADH2
- 8 NADH
- 8 H+
- 9 acetyl-CoA
- 120 ATP
As the cycle is repeated 8 times
What is the P/O ratio of FADH2
1.5
What is the P/O ratio of NADH + H+
2.5
Describe unsaturated fatty acids
- already partially oxidised
- yield less FADH2
Describe odd chain fatty chains
- yields propionyl-CoA in last step (3 carbon atoms)
- convert to succinyl-CoA
- enters TCA cycle directly
Describe branched chain fatty acids
- C1 carbon oxidised to CO2
- acetyl and propionyl-CoA released in equal numbers
Describe breakdown of glycerol
- activated to glycerol-3-phosphate by glycerol kinase present in liver and kidney but absent from adipose tissue, skeletal and heart muscle
- dehydrogenated to dihydroxyacetone phosphate, normal intermediate of carbohydrate metabolism
Ketosis in starvation or diabetes
- oxaloacetate in consumed for gluconeogenesis
- fatty acids are oxidised
- acetyl-CoA is converted to ketone bodies
- high levels in blood
- ketone bodies are moderate acids
- accumulation leads to severe acidosis (blood cant suffer any more)
- impairs tissue function, particularly central nervous system
- smell of acetone can be detected in breath
De novo synthesis of fatty acids occurs mainly where?
In the liver, kidney, mammary glands, adipose tissue and brain
When does de novo synthesis of fatty acids mainly take place?
During excess energy intake
What happens when excess carbohydrate is taken in?
- conversion of fatty acids and triglycerides in the liver
- free fatty acids are transported in plasma bound to albumin
- triglycerides formed in the liver are transported to adipose tissue by VLDL for storage
Lipogenesis is what type of process?
A reductive process, electrons are required
Synthesis of fatty acids from acetyl-CoA occurs where?
In the cytoplasm of liver cells
Acetyl CoA is generated where and by what?
Generated in mitochondria by pyruvate dehydrogenase complex
The inner mitochondrial membrane is impermeable to what?
Acetyl CoA
What transports acetyl groups into the cytoplasm?
Citrate
Citrate is formed from what?
- formed by condensation of acetyl-coA with oxaloacetate
- first step in TCA cycle
- when present in high concentrations, citrate is transported into the cytoplasm
What is the direct precursor of lipogenesis?
Malonyl-CoA
Describe the vital first step of lipogenesis
- acetyl CoA carboxylase is expressed mainly in liver and adipose tissue
- essential regulatory enzyme
- malonyl-CoA donates carbon atoms to new lipid
Describe fatty acid synthase
- catalyses synthesis of saturated long-chain fatty acids from malonyl-CoA, acetyl CoA and NADPH
- consists of a dimer of identical polypeptides, single polypeptide chain with seven distinct enzyme activities
- contain an acyl-carrier protein (ACP)
Name the three subunits of fatty acid synthase
- 4 release subunit
- 2 and 3 reduction and dehydration subunit
- condensation subunit
Describe lipogenesis by fatty acid synthase
- fatty acids are synthesised in a cycle of reactions
- using acetyl-CoA and malonyl-CoA as precursors, one cycle of reaction adds 2 carbon atoms to the growing acyl chain
- derived from malonyl-CoA
- growing acyl chain is attached to ACP
- requires NADPH as electron donor
When is the fatty acid released during lipogenesis by fatty acid synthase?
When a length of C-16 is reached
- palmitic acid (C16) is reached, the fatty acid is released by fatty acid synthase
Describe the control of fatty acid metabolism
- stringently controlled
- highly responsive to physiological needs
- synthesis is maximal when carbohydrate and energy are plentiful and when fatty acids are scarce
- essential role in regulating fatty acid synthesis and degradation; acetyl CoA carboxylase
- AMP kinase important
Describe regulation of Acetyl-CoA carboxylase
- INSULIN; signals the fed state, stimulate storage of fuels and synthesis of proteins
- GLUCAGON; signals the starved state
- EPINEPHRINE; signals requirement for energy; mobilise glycogen stores
- CITRATE; stimulates allosterically, citrate levels are high when acetyl-CoA and ATP are abundant
- antagonised by PALMITOYL-COA; abundant when fatty acids are in excess
Describe synthesis of triglycerides
- requires glycerol-3-phosphate (G3P)
- liver produces G-3-P from glycerol
- adipose tissue produce G-3-P from glucose
- adipose tissue production of triglycerides only during the fed state; insulin stimulates adipose tissue uptake of glucose
- triglyceride formation involves esterification
- liver also synthesises phospholipids, cholesterol and lipoproteins
What happens to amino acids which are not used as building blocks?
They are degraded - no storage for amino acids
Where is the major site of amino acid degradation?
The liver
Describe absorption of amino acids
- proteolytic enzymes in the stomach and intestine produce single amino acids and di and tri-peptides
- absorbed into intestinal cells and released into blood for absorption by other tissues
Describe protein turnover
- tightly regulated
- takes place at different rates; important for rapid changes
- damaged proteins have to be removed
Amino acids contain what?
- nitrogen
- some also contain nitrogen in the side chain
Amino acid breakdown produces what?
- ammonia (NH3)
- ammonium ion (NH4+)
Name the major nitrogen-containing excretory molecules
- urea; 80%, formed in the liver
- uric acid
- creatinine
- ammonium ion (NH4+)
Name the three steps in the synthesis of urea
- transamination
- de-animation
- urea (or ornithine) cycle
Describe transamination
- aminotransferases move the amino group from alpha amino acids to alpha keto acids
- usually alpha-keto glutarate, a TCA intermediate
- gives glutamate
- occurs in all tissues
Describe transamination for transport to the liver
- amino group of glutamate is transferred to pyruvate, giving alanine
- or glutamine synthase adds NH4+ to glutamate giving glutamine
Name the major carriers of nitrogen in the blood to liver
- alanine
- glutamine
Where does the deamination / urea cycle occur?
In the liver
Describe deamination / urea cycle
- amino group of glutamate is converted to free ammonium ion
- urea is synthesised in a complex series of reactions
- urea / ornithine cycle
- one nitrogen from free ammonium, the other from aspartic acid
- carbon from CO2
Describe the urea cycle stoichiometry
CO2 + NH4+ + 3 ATP + aspartate + 2 H20
urea + 2ADP + 2Pi + AMP + PPi +fumarate
Fumarate is an intermediate in the citrate cycle
Describe degradation of carbon skeletons
- after removal of alpha amino acid group, the remaining carbon skeletons are converted into major metabolic intermediates
- can be converted to glucose or oxidised in the TCA cycle
Describe degradation of ketogenic amino acids
- degraded to acetyl-CoA or acetoacetyl-CoA
- can give rise to ketone bodies or fatty acids
Describe degradation of glucogenic amino acids
- degraded to pyruvate or TCA cycle intermediates
- can be converted into phosphoenolpyruvate and then into glucose
Describe alkaptonuria
Degradation of phenylalanine and tyrosine is blocked
Describe maple syrup urine disease
- degradation of valine, isoleucine and leucine is blocked
- urine smells like maple syrup
- mental and physical retardation
- prevented by appropriate diet
Describe phenylketonuria
- phenylalanine accumulates in all body fluids
- leads to severe mental retardation if untreated
- therapy: low phenylalanine diet
Describe urea cycle disorders
- accumulation of urea cycle intermediates
- glutamine levels increase in the circulation
- alpha ketoglurarate is no longer regenerated
- alpha ketoglurarate levels become too low to fix more free ammonium ions
- elevated levels of ammonia in the blood are toxic for the nervous system
- treatment with low-protein diet
- drugs which remove nitrogen
- eg. forming complexes with amino acids which are excreted
- gene therapy in hepatocytes
