Metabolism 3 Flashcards
Glycogen
Storage form of glucose in ___
__ ATP for storage; ___ ATP for 1 glucose 6-P oxidized; ~ __% efficient
- You need one ATP to store glucose
- Breaking down 1 glucose gives you 30 ATP
What is the advantage to having a highly branched glycogen molecule?
- Increase ___ of ___ and ____
- Increase ___
Glycogen granules contain:
- ____ (~____glucose units)
- ____ for ___ and ___
- ____enzymes
Glycogen
Storage form of glucose in mammals
1 ATP for storage; 30 ATP for 1 glucose 6-P oxidized; ~ 97% efficient
You need one ATP to store glucose
Breaking down 1 glucose gives you 30 ATP
What is the advantage to having a highly branched glycogen molecule?
Increase rate of synthesis and degradation
Increase solubility
Glycogen granules contain:
Glycogen (~60,000 glucose units)
Enzymes for synthesis and degradation
Regulatory enzymes
Structure of glycogen
2 different linkages
___ main chain
___ branch points (Occur every ~__ residues)
Structure of glycogen
2 different linkages
α-1,4 main chain
α-1,6 branch points (Occur every ~10 residues)
Glycogen synthesis
Not a reversal of degradation
Biosynthetic & degradative pathways in biological systems are almost always distinct
Allows___
Glycogen synthesis
Not a reversal of degradation
Biosynthetic & degradative pathways in biological systems are almost always distinct
Allows control
Glycogen Synthesis
_____+ ___—> _____+ ____
UDP-Glucose
- ____ form
- Use ____
- ____ ____ drives the reaction (PPià2 Pi)
Glycogen Synthesis
UDP-Glucose
Activated form
Use UTP
Pyrophosphate hydrolysis drives the reaction (PPià2 Pi)
Glucose 1 Phosphate+ UTPà UDP-glucose+ PPi
Initiation of glycogen synthesis
_____ (GN)—enzyme catalyzes attachment of ____ to one of its own conserved ____ ___
- __ ___– _glucosyl units are linked to the protein
- Need “primer” like in DNA synthesis
- ____, evidence indicates that the two copies of the enzyme ____ one____
- They catalyze each other
Then you add _______ to ____ of __ glucose units
Initiation of glycogen synthesis
Glycogenin (GN)—enzyme catalyzes attachment of glucose to one of its own conserved tyrosine residuesSelf-priming – 8 glucosyl units are linked to the protein
Need “primer” like in DNA synthesis
Dimer, evidence indicates that the two copies of the enzyme glucosylate one another
They catalyze each other
Then you add UDP glucose to primer of 8 glucose units
Two Enzymes Involved in Glycogen Synthesis
- __ ___
- Uses ___ ___ to add ____ to main glycogen chain
- Forms ___ linkage
- Adds onto ____ in a linear chain
- __ ___
Two Enzymes Involved in Glycogen Synthesis
Glycogen synthase
Uses UDP-Glucose to add glucose to main glycogen chain
Forms α -1,4 linkage
Adds onto primer in a linear chain
Branching enzyme
Branching Enzyme
Creates a ____
____s α -1,4 linkage and forms ____ linkage (on another chain)
___ a block of ___ glucose residues
Branching Enzyme
Creates a branch
Breaks α -1,4 linkage and forms α -1,6 linkage (on another chain)
Transfers a block of 7 glucose residues
Tissue Localization
- Muscle:
- Used mainly to regenerate ___ during exercise
- ___–> ____ –> ____
- Liver:
- Supply glucose for ___ and ____
- Makes up ___% of liver cell
- ____–> ____ –> ____
- Liver has phosphatase to break down ___ –> ___
*
Tissue Localization
Muscle:
Used mainly to regenerate ATP during exercise
GlycogenàGlucoseàGlycolysis
Liver:
Supply glucose for brain, other tissues
Makes up 10% of liver cell
Glycogenà Glucose 6 PhosphateàGlucoseàBlood
Liver has phosphatase to break down glucose 6 phosphateàglucose
Breakdown of glycogen
Three enzymes are involved
- ___ ____
- Releases _______
- Important for breaking the ___ chain
- ____
- _____ ___ _____ (debranching enzyme)
- Releases____
- Breaks ____
- Transferase & debranching activity on a ____ polypeptide chain (Both important for breaking down __ __
Breakdown of glycogen
Three enzymes are involvedGlycogen phosphorylase
Releases glucose 1-phosphate
Important for breaking the linear chain
Transferase
α - 1,6 glucosidase (debranching enzyme)
Releases glucose
Breaks 1-6 linkage
Transferase & debranching activity on a single polypeptide chain (Both important for breaking down branch points
Glycogen Phosphorylase
- _____ at ___linkage
- Release ____
- Use ___ to break bond
- Not ____
- Glycosidic and ~P bond____ energy
- In vivo, the_____ _____ drives the reaction towards _____ of glycogen
- Glycogen (n residues) + Phosphate–> Glucose 1 Phosphate + Glycogen (n-1 residues)
Glycogen Phosphorylase
Phosphorolysis at α -1,4 linkage
Release glucose 1-P
Use phosphate to break bond
Not hydrolysis
Glycosidic and ~P bond similar energy
In vivo, the high [Pi] drives the reaction towards breakdown of glycogen
Glycogen (n residues) + PhosphateàGlucose 1 Phosphate + Glycogen (n-1 residues)
Transferase & α -1,6 Glucosidase
- Transfer of ___ glucose residues leaving only ___ glucose linked via ____ linkage
- α -1,6 Glucosidase
- Debranching enzyme
- Release of the ___ linked glucose as __ ___
- ____ reaction
Transferase & α -1,6 Glucosidase
Transfer of 3 glucose residues leaving only single glucose linked via α -1,6 linkage
α -1,6 Glucosidase
Debranching enzyme
Release of the a-1,6 linked glucose as free glucose
Hydrolysis reaction
Interconversion of Glucose 1-phosphate & Glucose 6-phosphate
Enzyme: ______
Present in ___ ___ ____
Function: generate ____for other pathways (____); ____ for ___ ___(and glycogen breakdown)
Interconversion of Glucose 1-phosphate & Glucose 6-phosphate
Enzyme phosphoglucomutase
Present in muscle, brain, liver
Function: generate glucose 6-P for other pathways (glycolysis); glucose 1-P for glycogen synthesis (and glycogen breakdown)
Glucose 6-phosphatase
A major function of the liver is to maintain a near constant level of glucose in the ____
Glucose is ___ a ___ ___ for the liver.
Glucose 6-phosphate is not ___ ____ out of the cell. Needs to be converted to____
Present in the___, but absent in the ___
Glucose 6-phosphatase
A major function of the liver is to maintain a near constant level of glucose in the blood
Glucose is not a major fuel for the liver.
Glucose 6-phosphate is not readily transported out of the cell. Needs to be converted to glucose
Present in the liver, but absent in the muscle
Role of glucose 6-phosphate
Glucose 6 Phosphate can be used for
____
___ ___
____
Role of glucose 6-phosphate
Glucose 6 Phosphate can be used for
Glycolysis
Free Glucose
PPP
Key points—regulation
- ____regulation of synthesis & breakdown (Avoidance of a ____ cycle)
- One is on while the other is off
- ___ and____
- ____ control through ___/____
- ___ ____ of glucose on ___ ___
Key points—regulation
Reciprocal regulation of synthesis & breakdown (Avoidance of a futile cycle)
One is on while the other is off
Covalent and allosteric
Hormonal control through phosphorylation/dephosphorylation
Allosteric effects of glucose on phosphorylase a
Control of glycogen synthesis & degradation
- Only one pathway active at a time
- Glycogen phosphorylase and glycogen synthase exist in different forms
- ___ (___ ___) and ____ (___ ___ ___) are involved
- No Phosphate
- Phosphorylase is_____ (__)
- Synthase is ____ (_ or _)
- Phosphorylated
- phosphorylase is ___ (_)
- Synthase is ___ (_ or _)
Control of glycogen synthesis & degradation
Only one pathway active at a time
Glycogen phosphorylase and glycogen synthase exist in different forms
Kinases (phosphorylase kinase) and phosphatases (protein phosphatase I) are involved
No Phosphate
Phosphorylase is inactive (b)
Synthase is active (I or a)
Phosphorylated
phosphorylase is active (a)
Synthase is inactive (D or b)
Regulation of glycogen metabolism via hormones
- Glucagon, epinephrine promote glycogen ____
- These hormones bind to receptors and activate ___ ___
- Elevated ______activates ________
- Resulting in the ____ of glycogen and inhibition of glycogen ____ via ____ and ____ of phosphorylase and synthetase respectively
- Insulin promotes ___ of glycogen by activating ____
- PPI _____ ___ ____ and _____, and activates ____
Regulation of glycogen metabolism via hormones
Glucagon, epinephrine promote glycogen degradation
These hormones bind to receptors and activate adenylate cyclase
Elevated cyclic AMP (cAMP) activates Protein Kinase A (PKA)
Resulting in the degradation of glycogen and inhibition of glycogen synthesis via activation and inhibition of phosphorylase and synthetase respectively
Insulin promotes synthesis of glycogen by activating PPI
PPI deactivates phosphorylase kinase and phosphorylase, and activates synthetase
Glycogen breakdown via β- adrenergic receptor activation
Glycogen breakdown via β- adrenergic receptor activation
α-Receptor mediated responses on phosphorylation
Epinephrine binds____
____ forms ___ and ___
They activate____ which will phosphorylate glygogen ____ and ____ __ ___.
IP3 can also work on ___ receptors which will release___
__ binds ____ which will bind a calmodulin dependent ____
Kinase will phosphorylate ___ ____ and shut it down
α-Receptor mediated responses on phosphorylation
Epinephrine binds GPCR
PIP2 forms IP3 and DAG
They activate PKC which will phosphorylate glygogen synthase and shut it down
IP3 can also work on ER receptors which will release Ca.
Ca binds Calmodulin which will bind a calmodulin dependent kinase
Kinase will phosphorylate Glycogen synthase and shut it down
Regulation of Protein Phosphatase 1 (PPI)
- Complex of PP1 consists of ___ components:
- ___
- ___ subunit (G subunit) confers__ ___ for ____
- _____- when ____, inhibits ___. (by binding to PP1)
- PPI is inactivated by
- Prevention of___ binding to ___
- ______ prevents catalytic activity of PPI
- RGI and Inhibitor I _____ by ____
- Active PKA will phosphorylate the ___ subunit so ___ can’t interact with ____
- If you inhibit PP1 ____ will always be active (its phosphorylated) and ____will be in inactive form
Regulation of Protein Phosphatase 1 (PPI)
Complex of PP1 consists of three components:
PP1
RGl subunit (G subunit) confers high affinity for glycogen
Inhibitor 1 - when phosphorylated, inhibits PP1. (by binding to PP1)
PPI is inactivated by
Prevention of RGI binding to PPI
Inhibitor I prevents catalytic activity of PPI
RGI and Inhibitor I activated by PKA
Active PKA will phosphorylate the RGI subunit so PPI can’t interact with glycogen
If you inhibit PP1 phosphorylase will always be active (its phosphorylated) and synthetase will be in inactive form
Phosphorylation reversed when cell needs to synthesize glycogen (have to activate the ____)
Phosphorylation reversed when cell needs to synthesize glycogen (have to activate the phosphatase)
Insulin regulation of glucose metabolism
Insulin will directly ____ PPI. Activated PPI will dephosphorylate the phosphorylase making it ____ and glycogen synthase making it ___
Promote glycogen ___ and shut down glycogen ____
Insulin binds to ___ receptor. Will be _____ and in turn will activate the insulin receptor substrate Y. Substrate will activate the ____ and inhibit ___ so PPI will be active
Insulin will directly Activate PPI. Activated PPI will dephosphorylate the phosphorylase making it inactive and glycogen synthase making it active.
Promote glycogen synthesis and shut down glycogen degradation.
Insulin binds to kinase receptor. Will be autophosphorylated and in turn will activate the insulin receptor substrate Y. Substrate will activate the phosphatase and inhibit PKA so PPI will be active
Glucose acts as an___ ____ of glycogen _____ a
High [glucose]: Binding to ____ sites
____ phosphate
Phosphate ____ (by PPI)
Phosphorylase __ less active (___glucose released)
When in active form the Phosphate groups are not presented enough.
Glucose will shut down degradation of glycogen
Negative allosteric modulation
Glucose acts as an allosteric modifier of glycogen phosphorylase a
High [glucose]: Binding to allosteric sites
Expose phosphate
Phosphate removed (by PPI)
Phosphorylase b less active (less glucose released)
When in active form the Phosphate groups are not presented enough.
Glucose will shut down degradation of glycogen
Negative allosteric modulation
Calcium & AMP also affect glycogen metabolism in the muscle
Release of Calcium from sarcoplasmic reticulum due to neural stimulation binds ____ which in turn activates ___ __
____ produced by degradation of ___ allosterically binds to phosphorylase__
Promote glycogen ____
Ca serves as stimulus to__ ___ stores of glycogen in the muscle
Ca Calmodulin activates ___ ___ which converts glycogen phosphorylase from ___ to ___ form
AMP assists in conversion from inactive form to the active form
Calcium & AMP also affect glycogen metabolism in the muscle
Release of Calcium from sarcoplasmic reticulum due to neural stimulation binds Calmodulin which in turn activates phosphorylase b
AMP produced by degradation of ATP allosterically binds to phosphorylase b
Promote glycogen degradation
Ca serves as stimulus to break down stores of glycogen in the muscle
Ca Calmodulin activates phosphorylase kinase which converts glycogen phosphorylase from inactive to active form
AMP assists in conversion from inactive form to the active form
Glycogen Metabolism Controls
Similar in muscle & liver for glycogen ____
- ____ [___] leads to increase in glycogen____
Muscle & liver differ for glycogen ____
- Liver—___ [____] stimulates glycogen ____ &___ ____
- Want to___ glucose into the blood stream
- Muscle—_____stimulates glycogen ___ and____
- Use glucose for Energy
Glycogen Metabolism Controls
Similar in muscle & liver for glycogen synthesis
High [glucose] leads to increase in glycogen synthase
Muscle & liver differ for glycogen breakdownLiver—low [glucose] stimulates glycogen breakdown & inhibits glycolysis
Want to release glucose into the blood stream
Muscle—Epinephrine stimulates glycogen breakdown and glycolysis
Use glucose for Energy
Glycogen Storage Diseases
There are complications if there are mutations in enzymes of synthesis and degradation
Glycogen Storage Diseases
There are complications if there are mutations in enzymes of synthesis and degradation
Summary
Glycogen synthesis and degradation are two ___ pathways.
Glycogen metabolism are controlled by____ effectors and by ____ modifications of glycogen phosphorylase and synthase
Main feature is ____ of enzymes
Hormones such as ____, ____ and____ regulate glycogen metabolism
Summary
Glycogen synthesis and degradation are two independent pathways.
Glycogen metabolism are controlled by allosteric effectors and by covalent modifications of glycogen phosphorylase and synthase
Main feature is phosphorylation of enzymes
Hormones such as epinephrine, glucagon and insulin regulate glycogen metabolism
Structure of fatty acids and triglycerols
Fatty Acid
Triglycerides: Glycerol backbone attached to 3 fa.
Structure of fatty acids and triglycerols
Fatty Acid
Triglycerides: Glycerol backbone attached to 3 fa.
Fatty acid synthesis
Formation of ___ ___
- _____, ____ step in fatty acid synthesis
- Catalyzed by ___ ___ ____
- Requires ____ as cofactor (_ step reaction)
____ + ___+ ___+ ___–> ____ + ___ + ____
Adds another ___ ___ to acetyl CoA
Fatty acid synthesis
Formation of Malonyl CoA
Irreversible, committed step in fatty acid synthesis
Catalyzed by acetyl CoA carboxylase
Requires biotin as cofactor (2 step reaction)
Acetyl CoA + CO2+ Biotin+ ATPà Malonyl CoA + ADP + Pi
Adds another carboxylic group to acetyl CoA
Acyl Carrier Protein (ACP)
____ + ___ ⇌ ______ + ____
____ _____
_____ + ___ ⇌ _____ + ___
____ _____
Acyl Carrier Protein (ACP)
Acetyl CoA + ACP ⇌ acetyl-ACP + CoA
acetyl transacylase
Malonyl CoA + ACP ⇌ malonyl-ACP + CoA
malonyl transacylase
Fatty Acid Synthase
____ complex-___
___ ___—allows ____synthesis of activities needed for Fatty acid synthesis
Specific ____ for each activity like a conveyer belt
__ ___ arm carries ____ from one site to another
Fatty Acid Synthase
Multienzyme complex-Dimer
Increase stability—allows coordinated synthesis of activities needed for Fatty acid synthesis
Specific domains for each activity like a conveyer belt
Flexible ACP arm carries substrates from one site to another
Fatty acid synthesis
4 reactions:
____
____
____
____
Requires ____
Fatty acid synthesis
4 reactions:
Condensation
Reduction
Dehydration
Reduction
Requires NADPH
Stoichiometry of fatty acid synthesis
____ + _____ + _____ +_____–>
____ + ____+ ____ + ___ + ____
_____ + ____ + ____–>____+ ___ + ___ + ___
Overall stoichiometry for palmitate synthesis (16 C)
_Acetyl CoA + _ ATP + _NADPH +_ H+ –> Palmitate + _ NADP+ + _ CoA + _ H2O + __ADP + _ Pi
Stoichiometry of fatty acid synthesis
Acetyl CoA + 7 malonyl CoA + 14 NADPH + 20 H+ à
Palmitate + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O
7 acetyl CoA + 7 CO2 + 7 ATP Ú 7 malonyl CoA + 7 ADP + 7 Pi + 14 H+
Overall stoichiometry for palmitate synthesis (16 C)
8 Acetyl CoA + 7 ATP + 14 NADPH + 6 H+ Ú Palmitate + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7 Pi
- Acetyl CoA must be translocated from _____ into ____
- Fatty acid synthesis occurs in ____
- Acetyl CoA formed in ____
- Mitochondria not permeable to ______
- Acetyl CoA transported in the form of ___
- _____ [citrate] in mitochondria results in increased ____ to cytosol
- Mitochondria: ________–>________
- Moves out of mitochondria
- Cytosol: _____–> ______
Acetyl CoA must be translocated from mitochondria into cytosol
Fatty acid synthesis occurs in cytosol
Acetyl CoA formed in mitochondria
Mitochondria not permeable to acetyl CoA
Acetyl CoA transported in the form of citrate
Increased [citrate] in mitochondria results in increased transport to cytosol
Acetyl CoA + Oxaloacetateà Citrate
Moves out of mitochondria
Citrateà Acetyl CoA + Oxaloacetate
Fatty acid transported to ____ to undergo β-oxidation
β oxidation will generate ___, _____(to be used in CAC)
Fats are stored as ___ in ___ cells
When they are broken down by _____
- Liver cell takes up ____, which can enter ____ or _____
- Other tissues take up the___ which can be ____ to ___ ___ and used in ____
Fatty acid transported to tissues to undergo β-oxidation
β oxidation will generate ATP, Acetyl CoA (to be used in CAC)
Fats are stored as TAG in fat cells
When they are broken down by lipases
Liver cell takes up Glycerol, which can enter Glycolysis or gluconeogenesis
Other tissues take up the fa which can be oxidized to acetyl coA and used in CAC
Fatty Acid Oxidation
β -oxidation of long chain (C___-C___) fatty acids occurs in ___ ___
Fatty acids linked to___ in an ____ ____ reaction
Activation of ____ group occurs on ___ ___ ___
- Enzyme: ___ ___ ___ ____
- ____+ ___ + ___–> ____ +___ + ___
Fatty Acid Oxidation
β -oxidation of long chain (C12-C20) fatty acids occurs in mitochondrial matrix
Fatty acids linked to CoA in an ATP dependent reaction
Activation of carboxyl group occurs on outer mitochondrial membrane
Fatty acyl CoA synthetase
Fatty acid + ATP + CoA à Fatty acyl-CoA + AMP + 2 Pi
Fatty acid entry into mitochondrial matrix Requires ____
Enzyme: ____ ___ ____
______ + _____ ⇌ _______ + ___
Fatty acid entry into mitochondrial matrix Requires Carnitine
Carnitine Acyl Transferase
Fatty Acyl CoA + carnitine ⇌ Fatty Acyl-carnitine + CoA
Translocation of Acyl carnitine
Transport by translocase
Carnitine Acyltransferase I to form ___ ___ in ____
Carnitine Acyltransferase II to ____ __ ___ in___
Translocation of Acyl carnitine
Transport by translocase
Carnitine Acyltransferase I to form acyl carnitine in cytoplasm
Carnitine Acyltransferase II to release acyl coA in matrix
β -oxidation of fatty acids
4 reactions: Basically reverse of fa synthesis
____
____
____
____ (There is S compound)
Break down fa in _C molecules (___ ___) and reduce fa by___ units
End result is ____ that go into ____
Oxidation of palmitate results in the generation of ___ATP molecules
β -oxidation of fatty acids
4 reactions: Basically reverse of fa synthesis
Oxidation
Hydration
Oxidation
Thiolysis (There is S compound)
Break down fa in 2C molecules (acetyl CoA) and reduce fa by 2 C units
End result is Acetyl CoA that go into CAC
Oxidation of palmitate results in the generation of 106 ATP molecules
Comparsion between fatty acid synthesis and degradation
Synthesis takes place in the____, while degradation takes place in the _____ ___
Intermediates in fatty acid synthesis are linked to an ___ ___ ___(___), whereas intermediates in fatty acid breakdown are attached to ___ ___
The enzymes of fatty acid synthesis in higher organisms are joined in a ____polypeptide chain called ___ __ ___. In contrast, the degradative enzymes do not seem to be ____
The ____ in fatty acid synthesis is ____, whereas the ____ in fatty acid degradation are ____ and ___
Comparsion between fatty acid synthesis and degradation
Synthesis takes place in the cytosol, while degradation takes place in the mitochondrial matrix
Intermediates in fatty acid synthesis are linked to an acyl carrier protein (ACP), whereas intermediates in fatty acid breakdown are attached to coenzyme A
The enzymes of fatty acid synthesis in higher organisms are joined in a single polypeptide chain called fatty acid synthase. In contrast, the degradative enzymes do not seem to be associated
The reductant in fatty acid synthesis is NADPH, whereas the oxidants in fatty acid degradation are NAD+ and FAD
Regulation of fatty acid metabolism
Fatty acids are synthesized and degraded by different pathways
- ____, ____ ___, ___
- Availability of these molecules will determine synthesis or degradation
Allows ____ regulation
___ ___ ____ key regulatory enzyme
In synthesis
Regulation of fatty acid metabolism
Fatty acids are synthesized and degraded by different pathwaysCarnitine, malonyl CoA, ACP
Availability of these molecules will determine synthesis or degradation
Allows reciprocal regulation
Acetyl CoA carboxylase key regulatory enzyme
In synthesis
Fatty acid Synthesis is regulated by
____ of ____ and when the level of ___ ___ are ___
The control of ___ ____ (____, ____ control)
Low fa: acetyl coA carboxylase tx will be ____
Fatty acid Synthesis is regulated by
Abundance of carbohydrate and when the level of fatty acids are low
The control of enzyme levels (degradation, transcriptional control)
Low fa: acetyl coA carboxylase tx will be upregulated
Control of Acetyl CoA carboxylase
- Enzyme activity
- 1.Activated by ____
- 2.Inhibited by synthesized ____
- 3.Energy charge
- If have low energy charge you get ____ of ___ ___ ___ ___
- Acetyl coA carboxylase will be ____ and ___ ___
- Need ____ amounts of ATP to synthesize fa
- 4.Insulin/glucagon ratio
- Insulin promotes ____ of fa
- Insulin promotes synthesis of macromolecules.
- Stimulates ___ of glycogen
- Excess sugar in liver will be converted to one form or another
- Next best thing is fa
- 5.Induction – ____ of enzyme change according to fed/starvation states
- Determined by__ ___
- Low fa, enzyme will be __ so you need to____tx of enzyme
- Starve: you ___ ____ to Syn fa. __ ___ tx of the enzyme
Control of Acetyl CoA carboxylase
Enzyme activity
- Activated by citrate
- Inhibited by synthesized long chain fatty acids
- Energy charge
If have low energy charge you get Activation of AMP activated protein kinase
Acetyl coA carboxylase will be phosphorylated and shut down
Need High amounts of ATP to synthesize fa
4.Insulin/glucagon ratio
Insulin promotes synthesis of fa
Insulin promotes synthesis of macromolecules.
Stimulates Syn of glycogen
Excess sugar in liver will be converted to one form or another
Next best thing is fa
5.Induction – quantity of enzyme change according to fed/starvation states
Determined by tx level
Low fa, enzyme will be low so you need to increase tx of enzyme
Starve: you don’t want to Syn fa. Shut down tx of the enzyme
Acetyl-CoA carboxylase phosphorylation/dephosphorylation
Activity turned ___ by phosphorylation
Allosteric effect of ____ (Stimulation) partially ____ ____ effect of phosphorylation by polymerization
Acetyl-CoA carboxylase phosphorylation/dephosphorylation
Activity turned OFF by phosphorylation
Allosteric effect of citrate (Stimulation) partially overcomes inhibition effect of phosphorylation by polymerization
Regulation of β -oxidation
Largely controlled by ____ of substrates
____ by adipose tissue ____
Inhibition of ___ ___ ____
Regulation of β -oxidation
Largely controlled by availability of substrates
Stimulation by adipose tissue lipases
Inhibition of carnitine acyl transferase
Co-ordinated regulation of fatty acid synthesis & degradation
Build up of malonyl CoA inhibits ___ ___ ____results in ___ uptake fatty acyl CoA for β -oxidation, while _____ fatty acid synthesis
Co-ordinated regulation of fatty acid synthesis & degradation
Build up of malonyl CoA inhibits Carnitine Acyl Transferase results in no uptake fatty acylCoA for β -oxidation, while promoting fatty acid synthesis
Ketone bodies
Produced from __ ___ when fat ___ predominates
In the liver Acetyl CoA from fa breakdown is converted to ____ and _____
Ketone bodies can be used as substitute for ____
Ketone bodies
Produced from acetyl CoA when fat breakdown predominates
In the liver Acetyl CoA from fa breakdown is converted to Acetoacetate and β -Hydroxybutyrate
Ketone bodies can be used as substitute for glucose
Synthesis of ketone bodies
____ major site of production
____ amount of ____limits the amount of acetyl CoA that can enter ___ ___ ___
_______ is the predominant end product
Acetyl CoA–> Acetoacetate–> β –Hydroxybutyrate + Acetone (ketone bodies)
Same for a diabetic patient: can’t __ ___glucose
Produce lots of acetyl CoA thru ____ and _____ of fats
Breath smells like ____
Synthesis of ketone bodies
Liver major site of production
Lowered amount of oxaloacetate limits the amount of acetyl CoA that can enter citric acid cycle
β -Hydroxybutyrate is the predominant end product
Acetyl CoAà Acetoacetateà β –Hydroxybutyrate + Acetone (ketone bodies)
Same for a diabetic patient: can’t take up glucose
Produce lots of acetyl CoA thru gluconeogenesis and break down of fats
Breath smells like acetone
Use of ketone bodies
- ____ acetyl CoA for metabolism by___ ___ ___
- Reactions in ___ ____
- Liver ___ ___ ___ ketone bodies as___source
- Lacks _-____-___ _____
- Can’t convert it back to _____ units
Use of ketone bodies
Re-form acetyl CoA for metabolism by Citric acid cycle
Reactions in mitochondrial matrix
Liver does not use ketone bodies as energy sourceLacks β -ketoacyl-CoA transferase
Can’t convert it back to acetyl coA units
___ ____determines rate of synthesis & usage
- Synthesis occurs when rates of ___ ___generation from β -oxidation of fatty acids exceed ____cycle flux
- To little oxaloacetate
- Ketone body utilization
- ___ ___ and ___ ____ use ___ ___ (when present) in preference to ___
- During conditions associated with prolonged ketone body generation (e.g. ____ and ___), organs adapt to ___ ____ on ketone bodies as a source of energy (e.g. brain)
- Fasting: Used up all glucose. Next best thing is fa breakdown. Create Acetyl CoA which is converted to ketone bodies
*
- Fasting: Used up all glucose. Next best thing is fa breakdown. Create Acetyl CoA which is converted to ketone bodies
Substrate availability determines rate of synthesis & usage
Synthesis occurs when rates of acetyl-CoA generation from β -oxidation of fatty acids exceed TCA cycle flux
To little oxaloacetate
Ketone body utilization
Resting muscle and renal cortex use ketone bodies (when present) in preference to glucose
During conditions associated with prolonged ketone body generation (e.g. fasting and starvation), organs adapt to increase reliance on ketone bodies as a source of energy (e.g. brain)
Fasting: Used up all glucose. Next best thing is fa breakdown. Create Acetyl CoA which is converted to ketone bodies
Interdependence of ketone body formation, fatty acid degradation & gluconeogenesis
In Liver, when blood glucose levels decrease (starvation) require _____of blood glucose levels
So,____peripheral tissue ___ of glucose &____ glucose production by____
Increase in ___, ___, ____ hormones & decrease in ____
Result: Increase ___ & _____supplies alternative fuels; Increase _____ in ___drives _____
First gluconeogenesis. Once that is exhausted, B oxidation comes into play
Brain can’t take up ___ directly
That’s why you need them in the form of ___ ___
It can only take up glucose and ketone bodies
Other tissues can take up___ easily.
Interdependence of ketone body formation, fatty acid degradation & gluconeogenesis
In Liver, when blood glucose levels decrease (starvation) require maintenance of blood glucose levels
So, decrease peripheral tissue use of glucose & increase glucose production by liver
Increase in glucagon, epinephrine, lipolytic hormones & decrease in insulin
Result: Increase lipolysis & ketogenesis supplies alternative fuels; Increase b-oxidation in liver drives gluconeogenesis
First gluconeogenesis. Once that is exhausted, B oxidation comes into play
Brain can’t take up fa directly
That’s why you need them in the form of ketone bodies.
It can only take up glucose and ketone bodies
Other tissues can take up fa easily.
Functions of Fatty Acids
Building blocks of _____ (sphingolipids and glycerophospholipids) and lipoproteins (myristate and phosphatidylinositol)
Source of _____ (triacylglycerols)
Precursors to ____ _____: Arachidonate (C-20, 4 double bonds) precursor for leukotrienes, prostaglandins (prostaglandin synthase)
Precursor for ___ ____ _____: Inositoltriphosphate (IP3) and Diacylgycerol
Functions of Fatty Acids
Building blocks of phospholipids (sphingolipids and glycerophospholipids) and lipoproteins (myristate and phosphatidylinositol)
Source of energy (triacylglycerols)
Precursors to hormones biosynthesis: Arachidonate (C-20, 4 double bonds) precursor for leukotrienes, prostaglandins (prostaglandin synthase)
Precursor for intracellular messenger biosynthesis: Inositoltriphosphate (IP3) and Diacylgycerol
Summary
Synthesis of fatty acids occurs in ___ using ___ ___ as activated donor of C2 units
___ ___ ___ is regulatory enzyme and highly regulated
B-oxidation occurs in ___ ___after activation of FA on ___ ___ ___
____transports FA into ____ and ____ ____regulates formation of FA-carnitine
Ketone bodies are produced from ___ ___ when fats breakdown predominates
Summary
Synthesis of fatty acids occurs in cytosol using malonyl CoA as activated donor of C2 units
Acetyl CoA Carboxylase is regulatory enzyme and highly regulated
B-oxidation occurs in mitochondrial matrix after activation of FA on outer mitochondrial membrane
Carnitine transports FA into matrix and malonyl CoA regulates formation of FA-carnitine
Ketone bodies are produced from acetyl CoA when fats breakdown predominates
Structure of Cholesterol
Consists
- ___ ___ ___
- A ___ ___
- A ____ group
- ____ ____ bond
- ___ ____ group
Structure of Cholesterol
Consists
- Four fused rings
- A hydrocarbon chain
- A Hydroxyl group
- A single double bond
- Two methyl group
Comes from ____ or ____ ____ Synthesis (we can synthesize them)
Role of Cholesterol:
____
____
___ ___
___ ___; ____
Comes from Diet or de novo Synthesis (we can synthesize them)
Role of Cholesterol:
Membranes
Excretion
Bile Acids
Steroid Hormones; Vitamins
Biosynthesis of Cholesterol
Synthesized in __ ___except ___ ___ __
Primary site of synthesis is ____
All carbons arise from ___ ___
Synthesis occurs in ___ & ___
2 Acetyl CoAà Acetoacetyl CoA by Acetoacetyl-CoA thiolase
Biosynthesis of Cholesterol
Synthesized in all tissues except red blood cells
Primary site of synthesis is LIVER
All carbons arise from Acetyl CoA
Synthesis occurs in cytosol & E.R.
2 Acetyl CoAà Acetoacetyl CoA by Acetoacetyl-CoA thiolase
HMG-CoA Synthase Acetoacetyl CoA+ Acetyl CoAà HMG-CoA
Two isoforms:
Mitochondrial enzyme: _____synthesis
Cytosolic enzyme: _____synthesis
HMG-CoA Synthase Acetoacetyl CoA+ Acetyl CoAà HMG-CoA
Two isoforms:
Mitochondrial enzyme: Ketone body synthesis
Cytosolic enzyme: Cholesterol synthesis
__-___ ______
Rate-limiting step in cholesterol biosynthesis
Occurs in the ___ ___ (____ face)
____ + ____–>____+ ____+ ____
HMG-CoA Reductase
Rate-limiting step in cholesterol biosynthesis
Occurs in the Endoplasmic reticulum (cytoplasmic face)
HMG CoA + 2NADPHà Mevalonate + 2 NADP+ + CoASH
Cholesterol synthesis
Mevalonate converted to isopentenyl pyrophosphate (C-_) in 3 steps
Requires _ ATP
Continued condensations, reductions to form Squalene (C-__)
C5 à C10 à C15 à C30
Lanosterol is the_____ intermediate derived from linear squalene
____ of __ methyl groups from lanosterol forms cholesterol (C___)
Requires __ enzymes, __, ____, ____
Mixed-function Oxygenases: Cytochrome ___
Mevalonateà5Cà30Cà cyclizeà 27 C Cholesterol
Cholesterol synthesis
Mevalonate converted to isopentenyl pyrophosphate (C-5) in 3 steps
Requires 3 ATP
Continued condensations, reductions to form Squalene (C-30)
C5 à C10 à C15 à C30
Lanosterol is the cyclized intermediate derived from linear squalene
Removal of 3 methyl groups from lanosterol forms cholesterol (C27)
Requires 20 enzymes, O2, NADPH, FAD
Mixed-function Oxygenases: Cytochrome P450
Mevalonateà5Cà30Cà cyclizeà 27 C Cholesterol
Regulation of HMG-CoA reductase
- Phosphorylation/dephosphorylation regulation
- Glucagon leads to ____ (___ form)
- Insulin leads to _____ (____ form) (Promotes synthesis)
- Increased [steroids] lead to ____ of proteolytic ____ of enzyme
- mRNA level regulated by cholesterol level
- ___[cholesterol] increases mRNA
- ____ [cholesterol] decreases mRNA
Regulation of HMG-CoA reductase
Phosphorylation/dephosphorylation regulation
Glucagon leads to phosphorylation (inactive form)
Insulin leads to dephosphorylation (active form) (Promotes synthesis)
Increased [steroids] lead to activation of proteolytic degradation of enzyme
mRNA level regulated by cholesterol level
Low [cholesterol] increases mRNA
High [cholesterol] decreases mRNA
HMG-CoA Reductase
Target of___-_____ drugs (_____ of cholesterol synthesis)
For people with high cholesterol
Use of ____-type drugs
- Lovastatin (Mevacor), Atorvastatin (Lipitor), simvastatin (Zocor)
- ___ ___
- Act as ___ ___ ____ inhibiting the fcn of they enzyme
HMG-CoA Reductase
Target of anti-cholesterol drugs (inhibition of cholesterol synthesis)
For people with high cholesterol
Use of Statin-type drugs
Lovastatin (Mevacor), Atorvastatin (Lipitor), simvastatin (Zocor)
Competitive inhibitors
Act as transition-state analogs inhibiting the fcn of they enzyme
Removal and Catabolism of Cholesterol
- ___ ___ & conversion to ___ sterols by_____ reduction (produced by bacteria in the gut)
- Excrete it in the bile and convert to neutral sterols
- Need to convert to ___ version so you can ____ it
- Excrete it in the bile and convert to neutral sterols
- Cholesterol converted to:
- ___ _____ packaged into the hollow core of ____, mainly ___ (Very low density lipoproteins)
- That’s how you move cholesterol from ___ to other sites in the body
- Cholesterol from diet moves from__ ___ to other sites in body
- ___ ___ and ___ ___
- Important for ___ of __
- Breakdown of complex fats.
- They don’t like water so you have to break them down to smaller particles so enzymes can attack them
- ___ ___
- ___ ___
- Cholesterol is ____ for Vitamin D
- ___ _____ packaged into the hollow core of ____, mainly ___ (Very low density lipoproteins)
Removal and Catabolism of Cholesterol
Biliary excretion & conversion to neutral sterols by bacterial reduction (produced by bacteria in the gut)Excrete it in the bile and convert to neutral sterols
Need to convert to milder version so you can excrete it
Cholesterol converted to:Cholesterol esters packaged into the hollow core of lipoproteins, mainly VLDL (Very low density lipoproteins)
That’s how you move cholesterol from liver to other sites in the body
Bile acids and bile salts
Important for emulsification of fats
Breakdown of complex fats.
They don’t like water so you have to break them down to smaller particles so enzymes can attack them
Steroid hormones
Vitamin D
Cholesterol is precursor for Vitamin D
Cholesterol from diet moves from small intestine to other sites in body
Bile Salts & Bile Acids
- ___ of cholesterol
- Cholesterol is ____ in ___ linkage with ___ or ___ (modified aa)
- Functions
- ____ of ___ cholesterol
- ____ of dietary fats
- Route of ____ of cholesterol
*
Bile Salts & Bile Acids
Derivatives of cholesterol
Cholesterol is conjugated in amide linkage with glycine or taurine (modified aa)
Functions
Solubilization of biliary cholesterol
Emulsification of dietary fats
Route of excretion of cholesterol
Synthesis of Bile Salts
Synthesized exclusively in____
Key rate limiting step - the conversion of cholesterol to __-_________ catalyzed by _-_____
Mixed function oxidase uses ___ as substrate (P450 enzymes)
Uses ____
Inhibited by ___ ___
End with ___ bile acids (chenocholic acid and cholic acid)
Synthesis of Bile Salts
Synthesized exclusively in LIVER
Key rate limiting step - the conversion of cholesterol to 7α-hydroxycholesterol catalyzed by 7α-Hydroxylase
Mixed function oxidase uses O2 as substrate (P450 enzymes)
Uses NADPH
Inhibited by bile salts
End with mixed bile acids (chenocholic acid and cholic acid)
Steroid Hormones Derived from Cholesterol
Requires __ & ___
Cholesterol–>____–>___–>____+ ____+_____and ____
Steroid Hormones Derived from Cholesterol
Requires O2 & NADPH
Cholesterol–>pregnenolone–>Progesterone–>glucocorticoid+ mineralcorticoid+Androgen and Estrogen
Formation of pregnenolone from cholesterol
Requires the enzyme ____
__ molecules of ____ and _____ are used in this reaction
Formation of pregnenolone from cholesterol
Requires the enzyme desmolase
3 molecules of NADPH and oxygen are used in this reaction
Pathways for the formation of Progesterone, ____ (glucocorticoid), and _____(mineralcorticoid)
Form from pregnenolone
Pathways for the formation for ___ and ____
Pathways for the formation of Progesterone, Cortisol (glucocorticoid), and Aldosterone (mineralcorticoid)
Form from pregnenolone
Pathways for the formation for Androgens and Estrogens
Vitamin D3: Regulate ____uptake & ____ loss
______ required for synthesis of vitamin D
Steps take place in __ ___ ___ (Liver, Kidney and Skin)
Inadequate D3 causes ____ (_____ of bones in children leading to fractures and deformities)
Vitamin D3: Regulate Calcium uptake & phosphate loss
UV light required for synthesis of vitamin D
Steps take place in 3 different organs (Liver, Kidney and Skin)
Inadequate D3 causes rickets (softening of bones in children leading to fractures and deformities)
Summary
Cholesterol synthesized from _______
________ key regulatory enzyme
Cholesterol used for biosynthesis of ____& ____
____ involving cholesterol metabolism.
Summary
Cholesterol synthesized from acetyl CoA
HMG CoA reductase key regulatory enzyme
Cholesterol used for biosynthesis of bile salts & steroid hormones.
Diseases involving cholesterol metabolism.
