Metabolism 4

Question 1

Lipid transport

• ____, ____, _____ transported as lipoproteins
  
  • Mainly in the ___ from site where you absorb fa like ____ to the___ where a lot of fa syn and storage and to ____ tissue
• __ ___ ___ transported by serum ____
  
  • In the blood

Answer 1

Lipid transport

Phospholipids, Triacylglycerols (TAGs), cholesterol transported as lipoproteins

Mainly in the blood from site where you absorb fa like intestines to the liver where a lot of fa syn and storage and to adipose tissue

Free fatty acids transported by serum albumin

In the blood

Question 2

Digestion of Fats in Foods

• ___ ____ cleave __ ___ off TAG’s at carbon _ & carbon _ in the ___ of the ___.
• Other____ remove carbon_ fa
• Fatty acids move through ____ _____ cells and combines with ____to form new ____’s
• Delivered as ____ through ___ system and____ to___ tissue
  
  • Combine with lipoproteins to form chylomicrons
• ____ (enzymes that breakdown TAGs) are activated on the __ ___ and they hydrolyze ___ to___ __ and ____, which are___ by the cells.
• Finally___for ___

Answer 2

Digestion of Fats in Foods

Pancreatic lipases cleave fatty acids off TAG’s at carbon 1 & carbon 3 in the lumen of the intestine.

Other esterases remove carbon 2 fa

Fatty acids move through intestinal epithelial cells and combines with glycerol to form new TAG’s

Delivered as chylomicrons through lymphatic system and bloodstream to peripheral tissue

Combine with lipoproteins to form chylomicrons

Lipases (enzymes that breakdown TAGs) are activated on the cell surfaces and they hydrolyze TAGs to fatty acids and glycerol, which are taken by the cells.

Finally oxidized for energy

Question 3

Lipoproteins

Defined by ___/___ratio

Higher protein/lipid ratio ____ the density) ___>___>___>___>____

H – High, I-Intermediate, L – Low and VL – Very Low Density Lipids

• LDL, IDL and VLDL
  
  • Transport ____ and ____ from the ___ to the ___
• Chylomicrons
  
  • ___ density
  • Transport ___ lipids from ____ to ___ cells
• HDL
  
  • Transports ___ from the ___ to the ___
• ___ ‘HDL/LDL’ besT

Answer 3

Lipoproteins

Defined by protein/lipid ratio

Higher protein/lipid ratio higher the densityHDL>LDL>IDL>VLDL>chylomicrons

H – High, I-Intermediate, L – Low and VL – Very Low Density Lipids

LDL, IDL and VLDL

Transport cholesterol and triglycerides from the liver to the tissues.

Chylomicrons

Lowest density

Transport dietary lipids from intestine to target cells

HDL

Transports cholesterol from the tissues to the liver

High ‘HDL/LDL’ best

Question 4

Lipoproteins

Lipoprotein particle structure

• Core ___ ___ (_____ and ___ ___)
• Outer shell of more___ ___ and___ (__-___)

2 functions

• ___ ____ lipids
• Contain __-___ signals

Answer 4

Lipoproteins

Lipoprotein particle structure

Core hydrophobic lipids (triacylglyerols and cholesterol esters)

Outer shell of more amphipathic lipids and proteins (apo-lipoproteins)

2 functions

Solubilize hydrophobic lipids

Contain cell-targeting signals

Question 5

VLDL

• VLDLs are synthesized in the ____
• Transported in the___
• At cell surfaces, ____ in VLDLs are acted on by ___ releasing___ ___
• __ ___ are taken up by the tissues.
• VLDL remnants remain in the ___ are converted to ___ and subsequently into ___
  
  • When fa are taken up by tissues
• IDL are converted to LDL in the blood by ___ _____
  
  • Add cholesterol and Add fa onto cholesterol

Answer 5

VLDL

VLDLs are synthesized in the liver

Transported in the blood

At cell surfaces, triacylglycerols in VLDLs are acted on by lipases releasing fatty acids

Fatty acids are taken up by the tissues.

VLDL remnants remain in the blood are converted to IDLs and subsequently into LDLs.

When fa are taken up by tissues

IDL are converted to LDL in the blood by cholesterol esterification.

Add cholesterol and Add fa onto cholesterol

Question 6

LDL Particle

• Major carrier of_____
  
  • ~1500 esterified molecules of cholesterol
• Mainly composed of ____-__
  
  • ____ molecule
  • Recognized by ___ on the___
  • It will dock onto the liver. Particle will be taken up by the liver and components will be recycled
• Function: Transportation of___ to ___ ___
• Regulates __ __ ___of ___ in___ ___

Answer 6

LDL Particle

Major carrier of cholesterol

~1500 esterified molecules of cholesterol

Mainly composed of Apoprotein-B

Signal molecule

Recognized by receptor on the liver

It will dock onto the liver. Particle will be taken up by the liver and components will be recycled

Function: Transportation of cholesterol to peripheral tissues

Regulates de novo synthesis of cholesterol in peripheral tissue

Question 7

HDL Particle

• __ __ released cholesterol from ___
  
  • ___ cells,___turnover
• Cholesterol ___ by _______
• Cholesterol Transferred from HDL to ___ or ____or returned to liver as ___

Answer 7

HDL Particle

Pick up released cholesterol from plasma

Dying cells, membrane turnover

Cholesterol esterified by acyltransferase

Cholesterol Transferred from HDL to VLDL or LDL or returned to liver as HDL

Question 8

Cholesterol metabolism

• Cholesterol in LDL particles containing apoprotein B
• ___ ____recognizes _______ _
• LDL particle ____ (receptor mediated endocytosis)
• Cholesterol___, LDL receptor ____
  
  • Primary source of ___ for cells other than ___ is the ____
• Particle is broken down. Get release of cholesterol and fa. Will be stored in ___
• Receptor dependent mediated endocytosis process

Answer 8

Cholesterol metabolism

Cholesterol in LDL particles containing apoprotein B

LDL receptor recognizes apo-protein B.

LDL particle endocytosed (receptor mediated endocytosis)

Cholesterol released, LDL receptor recycled

Primary source of cholesterol for cells other than liver is the intestine.

Particle is broken down. Get release of cholesterol and fa. Will be stored in liver.

Receptor dependent mediated endocytosis process

Question 9

Regulation of receptor mediated endocytosis

• Receptor subject to ___ ____
• When [cholesterol] high in cells, LDL-Receptor synthesis __ ___
  
  • Blocks additional cholesterol uptake
    
    • Don’t want to accumulate more cholesterol in the liver
  • ___ ____ by controlling rate of ____ synthesis

Answer 9

Regulation of receptor mediated endocytosis

Receptor subject to feedback regulation

When [cholesterol] high in cells, LDL-Receptor synthesis shut offBlocks additional cholesterol uptake

Don’t want to accumulate more cholesterol in the liver

Gene regulation by controlling rate of mRNA synthesis

Question 10

LDL Receptor Defects

Deficiency or dysfunction of LDL receptors leads to familial ______

Gene on chromosome 19

Dominantly inherited condition

Results in ____ LDL cholesterol levels in the___, premature _____ of coronary arteries

___types of mutations

LDL receptor is not produced

Mutation in terminal region;

Unable to bind LDL

Mutation in C-terminal region;

Prevents complex from undergoing endocytosis

Answer 10

LDL Receptor Defects

Deficiency or dysfunction of LDL receptors leads to familial hypercholesterolemia

Gene on chromosome 19

Dominantly inherited condition

Results in elevated LDL cholesterol levels in the blood, premature arteriosclerosis of coronary arteries

3 types of mutations

LDL receptor is not produced

Mutation in terminal region;

Unable to bind LDL

Mutation in C-terminal region;

Prevents complex from undergoing endocytosis

Question 11

Additional defects in cholesterol metabolism

_____ B-100

Genetic defect prevents ____ by receptor

Result is____ serum cholesterol

Tangier Disease

Lack of ATP-binding cassette protein, which ___ cholesterol out of cell

Cholesterol buildup in ___ & other organs

Answer 11

Additional defects in cholesterol metabolism

Apoprotein B-100

Genetic defect prevents recognition by receptor

Result is elevated serum cholesterol

Tangier Disease

Lack of ATP-binding cassette protein, which exports cholesterol out of cell

Cholesterol buildup in tonsils & other organs

Question 12

Summary

Lipoproteins defined by ____ ratio

Cholesterol taken into cell via __ __ ___

___ ___critical to cholesterol regulation

Answer 12

Summary

Lipoproteins defined by protein/lipid ratio

Cholesterol taken into cell via receptor mediated endocytosis

LDL receptor critical to cholesterol regulation

Question 13

Summary of amino acid metabolism

Dietary proteins are broken down by digestive enzymes to amino acid.

These amino acid are transported in the bloodstream to various tissues.

Amino acids are used for ___ ___ or they could be ___, since amino acids ___ be ___

During degradation, the _____ is removed and incorporated into ___ for excretion in terrestrial vertebrates.

The remaining carbon skeleton can used as ___ for____ intermediates, ___ generation, __ __ and ___ ___ formation.

Answer 13

Summary of amino acid metabolism

Dietary proteins are broken down by digestive enzymes to amino acid.

These amino acid are transported in the bloodstream to various tissues.

Amino acids are used for protein synthesis or they could be degraded, since amino acids CANNOT be stored.

During degradation, the α-amino group is removed and incorporated into urea for excretion in terrestrial vertebrates.

The remaining carbon skeleton can used as precursors for citric acid cycle intermediates, glucose generation, fatty acid and ketone body formation.

Question 14

Removal of the alpha-amino group (transamination)

To enter metabolic pathways for energy generation, ___ must first be ____ and disposed.

Occurs in 2 Steps

1.Transfer of ______ to ____ to form ____. The resulting ____ can be used to generate ____ in some tissues.

2____ is ___ly ____ed to form____ using ___(___ is generated)

Answer 14

Removal of the alpha-amino group (transamination)

To enter metabolic pathways for energy generation, Nitrogen must first be removed and disposed.

Occurs in 2 Steps

1. Transfer of α-amino group to α-ketoglutarate to form glutamate. The resulting α-ketoacid can be used to generate energy in some tissues.
2. Glutamate is oxidatively deaminated to form ammonia (NH4) using NAD+ (NADH is generated)

Question 15

Transaminases (aminotransferases)

Enzymes that transfer _____from an ____ to form an ____

Contains the coenzyme ____ ____

Enzymes are found in ___ and ____

Aspartate transaminase
Aspartate + ____ —> ____ + ____

Alanine transaminase

Alanine + _____ –>___+ ___

Each aa has a corresponding transaminase

Answer 15

Transaminases (aminotransferases)

Enzymes that transfer α -amino group from an amino acid to form an α -keto acid

Contains the coenzyme Pyridoxal Phosphate

Enzymes are found in cytoplasm and mitochondria

Aspartate transaminase
Aspartate + α -ketoglutarate ßàoxaloacetate + glutamate

Alanine transaminase

Alanine + α -ketoglutarateßàpyruvate + glutamate

Each aa has a corresponding transaminase

Question 16

Regeneration of a-Ketoglutarate

___ _____ catalyzes oxidative deamination of____ to form ____

______ is regenerated for future Transaminase reactions.

Can use either ___ or ___

Enzyme is found only in ____

Answer 16

Regeneration of a-Ketoglutarate

Glutamate Dehydrogenase catalyzes oxidative deamination of glutamate to form NH4+

α -ketoglutarate is regenerated for future Transaminase reactions.

Can use either NAD+ or NADP+

Enzyme is found only in mitochondria

Question 17

Regulation of Glutamate Dehydrogenase

+ ___ ____

• ___ ____

Removal of ____ drives the forward reaction (glutamate to a-ketoglutarate)

The availability of ____

Allosteric control:

___ and ____ inhibits glutamate dehydrogenase

___ and ___ reverse inhibition of glutamate dehydrogenase (When the energy charge is low, glutamate dehydrogenase is ____ leading to ____ of amino acids. The resulting carbon skeleton feeds into citric acid cycle ultimately generating energy by oxidative phosphorylation

Answer 17

Regulation of Glutamate Dehydrogenase

+ GDP, ADP

• GTP, ATP

Removal of NH4+ drives the forward reaction (glutamate to a-ketoglutarate)

The availability of NAD+

Allosteric control:

GTP & ATP inhibits glutamate dehydrogenase

GDP & ADP reverse inhibition of glutamate dehydrogenase (When the energy charge is low, glutamate dehydrogenase is activated leading to oxidation of amino acids. The resulting carbon skeleton feeds into citric acid cycle ultimately generating energy by oxidative phosphorylation

Question 18

Nitrogen from amino acids transported to liver as ____ & ____

Transport of nitrogen from generated form the degradation of amino acids in the muscle and peripheral tissues

Amino acid degradation occurs in ___ ____

However, urea production only takes place in the ____

The nitrogen generated by the degradation of amino acids in tissues has to be transported to the ___ for urea production.

___ and ___ are the major carriers of nitrogen in the blood.

Alanine is primarily exported by the ___because ____ produced by glycolysis is transaminated by ____ to ____

In the liver alanine is transaminated back to ____ (glucose production through ____ and nitrogen for ____ production)

In the muscle and the peripheral tissues, ____ is synthesized from glutamate by the enzyme ___ ____(requiring ____)

Glutamine transported to the liver is converted to glutamate by _____ releasing ammonia in the form of ___

Glutamate generated in above reactions is further converted to____ releasing ___.

The two molecules of NH4+ generated are used to produce ___ for excretion via the ____ as urine.

Answer 18

Nitrogen from amino acids transported to liver as alanine & glutamine

Transport of nitrogen from generated form the degradation of amino acids in the muscle and peripheral tissues

Amino acid degradation occurs in all tissues.

However, urea production only takes place in the liver.

The nitrogen generated by the degradation of amino acids in tissues has to be transported to the liver for urea production.

Alanine and glutamine are the major carriers of nitrogen in the blood.

Alanine is primarily exported by the muscle because pyruvate produced by glycolysis is transaminated by glutamate to alanine.

In the liver alanine is transaminated back to pyruvate (glucose production through gluconeogenesis and nitrogen for urea production)

In the muscle and the peripheral tissues, glutamine is synthesized from glutamate by the enzyme glutamine synthetase (requiring ATP)

Glutamine transported to the liver is converted to glutamate by glutaminase releasing ammonia in the form of NH4+

Glutamate generated in above reactions is further converted to a-ketoglutarate releasing NH4+.

The two molecules of NH4+ generated are used to produce urea for excretion via the kidneys as urine.

Question 19

Urea Cycle—In Liver

____ is toxic to the body particularly to the ___ and __ ___

Ammonia is converted to urea and excreted as urine in humans.

Reactions in ___ & ___ of ___

Total of __ (hydrolysis of _ATP and _ ___) to synthesize urea.

You also need ___ and ____

Answer 19

Urea Cycle—In Liver

Ammonia is toxic to the body particularly to the brain and spinal cord.

Ammonia is converted to urea and excreted as urine in humans.

Reactions in cytosol & mitochondria of liver.

Total of 4 ~P (hydrolysis of 3ATP and 1 PPi) to synthesize urea.

You also need CO2 and Aspartate

Question 20

Production of carbamoyl phosphate

___ step of the urea cycle (rate limiting step).

Formation of carbamoyl phosphate by the enzyme ___ ___ ___ __

Found in ____

Requires __ ATP to synthesis _ molecule of carbamoyl phosphate

___+ ___==> ____ + ___+ ____=> ___ + ____ + ____

Answer 20

Production of carbamoyl phosphate

First step of the urea cycle (rate limiting step).

Formation of carbamoyl phosphate by the enzyme carbamoyl phosphate synthetase I

Found in Mitochondria

Requires 2 ATP to synthesis 1 molecule of carbamoyl phosphate

CO2+ H20à HCO3- + NH4 + 2 ATPà Carbamoyl Phosphate+ 2ADP + 2Pi

Question 21

Urea Cycle

Note: You produce ____

Fumarate links urea cycle & ______

Fumarate produced by the cleavage of ____ is converted to ___(by ___) which is used to synthesis _____ (intermediates of citric acid cycle).

Oxaloacetate has several possible fates:

(1) ____ to ____ (aspartate produced feeds into the ___ ___),
(2) Conversion into ____ by the gluconeogenic pathway,
(3) Condensation with ____ __to form ___, or
(4) Conversion into ____

Answer 21

Urea Cycle

Note: You produce Fumarate

Fumarate links urea cycle & citric acid cycle

Fumarate produced by the cleavage of Argininosuccinate is converted to malate (by fumarase) which is used to synthesis oxaloacetate (intermediates of citric acid cycle).

Oxaloacetate has several possible fates:

(1) Transamination to aspartate (aspartate produced feeds into the urea cycle),
(2) Conversion into glucose by the gluconeogenic pathway,
(3) Condensation with acetyl CoA to form citrate, or
(4) Conversion into pyruvate.

Question 22

Regulation of the urea cycle

Availability of substrate; higher the rate of ammonia produced the ___ the rate of urea formation.

Allosteric activation

• _____ stimulates carbamoyl phosphate synthetase I (rate limiting step of the urea cycle)

Induction and repression of the urea cycle enzymes (___ and ____ of enzymes and control of____)

• Based on availability of substrates

Cycle enzymes are ___ under conditions such as:

• ___-protein diet
  
  • Produce a lot of urea
• Prolonged____
  
  • First use glycogen, then fa, and lastly break down aa
  • Produce ammonia and stimulate pathway

Under both conditions amino acids are converted to ____(carbon skeleton) and ____(nitrogen).

Answer 22

Regulation of the urea cycle

Availability of substrate; higher the rate of ammonia produced the higher the rate of urea formation.

Allosteric activation

N-Acetylglutamate stimulates carbamoyl phosphate synthetase I (rate limiting step of the urea cycle)

Induction and repression of the urea cycle enzymes (synthesis and degradation of enzymes and control of transcription)

Based on availability of substrates

Cycle enzymes are induced under conditions such as:

High-protein diet

Produce a lot of urea

Prolonged fasting

First use glygen, then fa, and lastly break down aa

Produce ammonia and stimulate pathway

Under both conditions amino acids are converted to glucose (carbon skeleton) and urea (nitrogen).

Question 23

N-Acetylglutamate (NAG)

• ___ + ____–>NAG
  
  • Enzyme: ___ ____
• Activates CPSI
• No other ___ ____
• NAG is produced from acetyl CoA and glutamate
• ___ stimulates NAG synthase
• When arginine levels increase within the liver
  
  • ___ synthesis of NAG results in ___ levels of carbamoyl phosphate production
  • Production of more ___ via the ___ reaction results in rapid operation of the urea cycle.
    *

Answer 23

N-Acetylglutamate (NAG)

Glutamate + Acetyl CoAàNAG

Enzyme: NAG Synthase

Activates CPSI

No other known function

NAG is produced from acetyl CoA and glutamate

Arginine stimulates NAG synthase

When arginine levels increase within the liver

Increased synthesis of NAG results in higher levels of carbamoyl phosphate production

Production of more ornithine via the arginase reaction results in rapid operation of the urea cycle.

Question 24

Hyperammonemia

High levels of ammonia toxic to humans (damage to brain and spinal cord)

Defects in enzymes of the urea cycle result in ____ of ____ and ____ levels in the ____.

Inherited disorders with partial deficiencies found in all enzymes of urea cycle

Deficiency in ____ also leads to hyperammonemia

Treatment

• ___diagnosis, aggressive use of compounds that can ___ ___
• ___ protein diets can reduce the level of amino acid degradation.

Answer 24

Hyperammonemia

High levels of ammonia toxic to humans (damage to brain and spinal cord)

Defects in enzymes of the urea cycle result in elevation of ammonia and glutamine levels in the blood.

Inherited disorders with partial deficiencies found in all enzymes of urea cycle

Deficiency in NAGS also leads to hyperammonemia

Treatment

Early diagnosis, aggressive use of compounds that can remove nitrogen.

Low protein diets can reduce the level of amino acid degradation.

Question 25

Fate of carbon atoms

• Give rise to major ___ ___
• 20 amino acids degraded to __ carbon skeletons
• Amino acids that are degraded to ___, ____, ___, ___, or ____ are termed ____ amino acids.
• Amino acids that form ___, ____ are known as_____ amino acids
  *

Answer 25

Fate of carbon atoms

Give rise to major metabolic intermediates

20 amino acids degraded to 7 carbon skeletons

Amino acids that are degraded to pyruvate, a-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate are termed glucogenic amino acids.

Amino acids that form acetyl CoA, acetoacetyl CoA are known as Ketogenic amino acids

Question 26

Summary

Urea is synthesized in the ___

Amino acids ___ and ____ carry amino acid nitrogen from the peripheral tissues to the ____

The urea cycle incorporates nitrogen from ____ and from____ into urea in 4 steps.

Answer 26

Summary

Urea is synthesized in the liver.

Amino acids alanine and glutamine carry amino acid nitrogen from the peripheral tissues to the liver.

The urea cycle incorporates nitrogen from ammonia and from aspartate into urea in 4 steps.