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Biomedical Sciences Core > Metabolism 3 > Flashcards

Metabolism 3 Flashcards

1
Q

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
A

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

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2
Q

Structure of glycogen

2 different linkages

___ main chain

___ branch points (Occur every ~__ residues)

A

Structure of glycogen

2 different linkages

α-1,4 main chain

α-1,6 branch points (Occur every ~10 residues)

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3
Q

Glycogen synthesis

Not a reversal of degradation

Biosynthetic & degradative pathways in biological systems are almost always distinct

Allows___

A

Glycogen synthesis

Not a reversal of degradation

Biosynthetic & degradative pathways in biological systems are almost always distinct

Allows control

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4
Q

Glycogen Synthesis

_____+ ___—> _____+ ____

UDP-Glucose

  • ____ form
  • Use ____
  • ____ ____ drives the reaction (PPià2 Pi)
A

Glycogen Synthesis

UDP-Glucose

Activated form

Use UTP

Pyrophosphate hydrolysis drives the reaction (PPià2 Pi)

Glucose 1 Phosphate+ UTPà UDP-glucose+ PPi

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5
Q

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

A

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

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6
Q

Two Enzymes Involved in Glycogen Synthesis

  • __ ___
    • Uses ___ ___ to add ____ to main glycogen chain
    • Forms ___ linkage
    • Adds onto ____ in a linear chain
  • __ ___
A

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

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7
Q

Branching Enzyme

Creates a ____

____s α -1,4 linkage and forms ____ linkage (on another chain)

___ a block of ___ glucose residues

A

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

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8
Q

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 ___ –> ___
      *
A

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

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9
Q

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 __ __
A

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

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10
Q

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)
A

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)

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11
Q

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
A

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

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12
Q

Interconversion of Glucose 1-phosphate & Glucose 6-phosphate

Enzyme: ______

Present in ___ ___ ____

Function: generate ____for other pathways (____); ____ for ___ ___(and glycogen breakdown)

A

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)

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13
Q

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 ___

A

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

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14
Q

Role of glucose 6-phosphate

Glucose 6 Phosphate can be used for

____

___ ___

____

A

Role of glucose 6-phosphate

Glucose 6 Phosphate can be used for

Glycolysis

Free Glucose

PPP

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15
Q

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 ___ ___
A

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

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16
Q

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 _)
A

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)

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17
Q

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 ____
A

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

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18
Q

Glycogen breakdown via β- adrenergic receptor activation

A

Glycogen breakdown via β- adrenergic receptor activation

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19
Q

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

A

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

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20
Q

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
A

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

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21
Q

Phosphorylation reversed when cell needs to synthesize glycogen (have to activate the ____)

A

Phosphorylation reversed when cell needs to synthesize glycogen (have to activate the phosphatase)

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22
Q

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

A

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

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23
Q

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

A

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

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24
Q

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

A

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

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25
Q

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
A

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

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26
Q

Glycogen Storage Diseases

There are complications if there are mutations in enzymes of synthesis and degradation

A

Glycogen Storage Diseases

There are complications if there are mutations in enzymes of synthesis and degradation

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27
Q

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

A

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

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28
Q

Structure of fatty acids and triglycerols

Fatty Acid

Triglycerides: Glycerol backbone attached to 3 fa.

A

Structure of fatty acids and triglycerols

Fatty Acid

Triglycerides: Glycerol backbone attached to 3 fa.

29
Q

Fatty acid synthesis

Formation of ___ ___

  • _____, ____ step in fatty acid synthesis
  • Catalyzed by ___ ___ ____
  • Requires ____ as cofactor (_ step reaction)

____ + ___+ ___+ ___–> ____ + ___ + ____

Adds another ___ ___ to acetyl CoA

A

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

30
Q

Acyl Carrier Protein (ACP)

____ + ___ ⇌ ______ + ____

____ _____

_____ + ___ ⇌ _____ + ___

____ _____

A

Acyl Carrier Protein (ACP)

Acetyl CoA + ACP ⇌ acetyl-ACP + CoA

acetyl transacylase

Malonyl CoA + ACP ⇌ malonyl-ACP + CoA

malonyl transacylase

31
Q

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

A

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

32
Q

Fatty acid synthesis

4 reactions:

____

____

____

____

Requires ____

A

Fatty acid synthesis

4 reactions:

Condensation

Reduction

Dehydration

Reduction

Requires NADPH

33
Q

Stoichiometry of fatty acid synthesis

____ + _____ + _____ +_____–>

____ + ____+ ____ + ___ + ____

_____ + ____ + ____–>____+ ___ + ___ + ___

Overall stoichiometry for palmitate synthesis (16 C)

_Acetyl CoA + _ ATP + _NADPH +_ H+ –> Palmitate + _ NADP+ + _ CoA + _ H2O + __ADP + _ Pi

A

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

34
Q
  • 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: _____–> ______
A

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

35
Q

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 ____
A

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

36
Q

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: ___ ___ ___ ____
  • ____+ ___ + ___–> ____ +___ + ___
A

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

37
Q

Fatty acid entry into mitochondrial matrix Requires ____

Enzyme: ____ ___ ____

______ + _____ ⇌ _______ + ___

A

Fatty acid entry into mitochondrial matrix Requires Carnitine

Carnitine Acyl Transferase

Fatty Acyl CoA + carnitine ⇌ Fatty Acyl-carnitine + CoA

38
Q

Translocation of Acyl carnitine

Transport by translocase

Carnitine Acyltransferase I to form ___ ___ in ____

Carnitine Acyltransferase II to ____ __ ___ in___

A

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

39
Q

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

A

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

40
Q

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 ___

A

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

41
Q

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

A

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

42
Q

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 ____

A

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

43
Q

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
A

Control of Acetyl CoA carboxylase

Enzyme activity

  1. Activated by citrate
  2. Inhibited by synthesized long chain fatty acids
  3. 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

44
Q

Acetyl-CoA carboxylase phosphorylation/dephosphorylation

Activity turned ___ by phosphorylation

Allosteric effect of ____ (Stimulation) partially ____ ____ effect of phosphorylation by polymerization

A

Acetyl-CoA carboxylase phosphorylation/dephosphorylation

Activity turned OFF by phosphorylation

Allosteric effect of citrate (Stimulation) partially overcomes inhibition effect of phosphorylation by polymerization

45
Q

Regulation of β -oxidation

Largely controlled by ____ of substrates

____ by adipose tissue ____

Inhibition of ___ ___ ____

A

Regulation of β -oxidation

Largely controlled by availability of substrates

Stimulation by adipose tissue lipases

Inhibition of carnitine acyl transferase

46
Q

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

A

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

47
Q

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 ____

A

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

48
Q

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 ____

A

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

49
Q

Use of ketone bodies

  • ____ acetyl CoA for metabolism by___ ___ ___
  • Reactions in ___ ____
  • Liver ___ ___ ___ ketone bodies as___source
    • Lacks _-____-___ _____
    • Can’t convert it back to _____ units
A

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

50
Q

___ ____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
        *
A

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

51
Q

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.

A

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.

52
Q

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

A

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

53
Q

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

A

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

54
Q

Structure of Cholesterol

Consists

  1. ___ ___ ___
  2. A ___ ___
  3. A ____ group
  4. ____ ____ bond
  5. ___ ____ group
A

Structure of Cholesterol

Consists

  1. Four fused rings
  2. A hydrocarbon chain
  3. A Hydroxyl group
  4. A single double bond
  5. Two methyl group
55
Q

Comes from ____ or ____ ____ Synthesis (we can synthesize them)

Role of Cholesterol:

____

____

___ ___

___ ___; ____

A

Comes from Diet or de novo Synthesis (we can synthesize them)

Role of Cholesterol:

Membranes

Excretion

Bile Acids

Steroid Hormones; Vitamins

56
Q

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

A

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

57
Q

HMG-CoA Synthase Acetoacetyl CoA+ Acetyl CoAà HMG-CoA

Two isoforms:

Mitochondrial enzyme: _____synthesis

Cytosolic enzyme: _____synthesis

A

HMG-CoA Synthase Acetoacetyl CoA+ Acetyl CoAà HMG-CoA

Two isoforms:

Mitochondrial enzyme: Ketone body synthesis

Cytosolic enzyme: Cholesterol synthesis

58
Q

__-___ ______

Rate-limiting step in cholesterol biosynthesis

Occurs in the ___ ___ (____ face)

____ + ____–>____+ ____+ ____

A

HMG-CoA Reductase

Rate-limiting step in cholesterol biosynthesis

Occurs in the Endoplasmic reticulum (cytoplasmic face)

HMG CoA + 2NADPHà Mevalonate + 2 NADP+ + CoASH

59
Q

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

A

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

60
Q

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
A

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

61
Q

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
A

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

62
Q

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
  • 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
A

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

63
Q

Bile Salts & Bile Acids

  • ___ of cholesterol
    • Cholesterol is ____ in ___ linkage with ___ or ___ (modified aa)
  • Functions
    • ____ of ___ cholesterol
    • ____ of dietary fats
    • Route of ____ of cholesterol
      *
A

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

64
Q

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)

A

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)

65
Q

Steroid Hormones Derived from Cholesterol

Requires __ & ___

Cholesterol–>____–>___–>____+ ____+_____and ____

A

Steroid Hormones Derived from Cholesterol

Requires O2 & NADPH

Cholesterol–>pregnenolone–>Progesterone–>glucocorticoid+ mineralcorticoid+Androgen and Estrogen

66
Q

Formation of pregnenolone from cholesterol

Requires the enzyme ____

__ molecules of ____ and _____ are used in this reaction

A

Formation of pregnenolone from cholesterol

Requires the enzyme desmolase

3 molecules of NADPH and oxygen are used in this reaction

67
Q

Pathways for the formation of Progesterone, ____ (glucocorticoid), and _____(mineralcorticoid)

Form from pregnenolone

Pathways for the formation for ___ and ____

A

Pathways for the formation of Progesterone, Cortisol (glucocorticoid), and Aldosterone (mineralcorticoid)

Form from pregnenolone

Pathways for the formation for Androgens and Estrogens

68
Q

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)

A

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)

69
Q

Summary

Cholesterol synthesized from _______

________ key regulatory enzyme

Cholesterol used for biosynthesis of ____& ____

____ involving cholesterol metabolism.

A

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.

Biomedical Sciences Core (55 decks)

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