Metabolism 4 Flashcards
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
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
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 ___
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
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
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
Lipoproteins
Lipoprotein particle structure
- Core ___ ___ (_____ and ___ ___)
- Outer shell of more___ ___ and___ (__-___)
2 functions
- ___ ____ lipids
- Contain __-___ signals
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
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
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
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___ ___
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
HDL Particle
- __ __ released cholesterol from ___
- ___ cells,___turnover
- Cholesterol ___ by _______
- Cholesterol Transferred from HDL to ___ or ____or returned to liver as ___
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
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
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
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
- Blocks additional cholesterol uptake
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
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
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
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
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
Summary
Lipoproteins defined by ____ ratio
Cholesterol taken into cell via __ __ ___
___ ___critical to cholesterol regulation
Summary
Lipoproteins defined by protein/lipid ratio
Cholesterol taken into cell via receptor mediated endocytosis
LDL receptor critical to cholesterol regulation
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.
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.
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)
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
- Transfer of α-amino group to α-ketoglutarate to form glutamate. The resulting α-ketoacid can be used to generate energy in some tissues.
- Glutamate is oxidatively deaminated to form ammonia (NH4) using NAD+ (NADH is generated)
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
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
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 ____
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
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
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
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.
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.
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 ____
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
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
___+ ___==> ____ + ___+ ____=> ___ + ____ + ____
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
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 ____
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.
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).
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).
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.
*
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.
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.
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.
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
*
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
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.
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.
