Biochem Final Review Flashcards
What is the function of cholesterol in the body?
component of cell membranes that modulate fluidity
in specialized tissue as a precursor of bile acids, steroid hormones, and vitamin D
ensure continuous supply of transport, biosynthetic and regulatory mechanisms
What organ plays the central role in regulations of the body’s cholesterol homeostasis?
liver
What layer of the membrane is cholesterol found?
both layers
What are the sources of cholesterol that enter the liver’s cholesterol pool?
dietary cholesterol
de novo synthesis by extrahepatic tissues
de novo sythesis by the lvier itself
How is cholesterol eliminated from the liver?
as unmodified cholesterol in the bile
converted to bile salts that are secreted into the intestinal lumen
sent to the peripheral tissues
With good circulation, how much cholesterol would we retain from intestinal digestion?
about 90%
What are the consequences of cholesterol imbalance?
deposition in the tissues particularly in the endothelial lining of blood vessels that lead to plaque formation causing narrowing blood vessels, atherosclerosis and increased CAD risk
When transported around the body, the plasma cholesterol form is _______.
esterified in lipoproteins
Detail cholesterol synthesis.
synthesized by virtually all tissues, esp the liver, intestine, adrenal cortex and reproductive tissues
all carbons are provided by acetate
NADPH is the reducing equivalents
synthesis occurs in the cytoplasma where the enzymes are in the cytosol and ER
The pathway is responsive to cholesterol conc such that regulatory mechanisms exist to balance the rate of cholesterol synthesis within the body against the rate of excretion
Because the de novo synthesis takes alot of effort, we try to retain as much as possible.
Detail how HMG-CoA is synthesized
2 acetyl CoAs are put together by thiolase and a third is added to make HMG CoA by HMG-CoA synthase
this is the first two steps of cholesterol synthesis
What is the rate-limiting step of cholesterol?
HMG CoA reductase that takes HMG CoA to mevalonic acid using two NADPH equivalents
What are the regulation points of cholesterol synthesis?
- SREBP controls the HMG CoA reductase gene such that bound SREBP causes increased expression when cholesterol levels are low
- protein and mRNA stability where cholesterol presence decreases the stability and increases the degradation
- phosphorylation/ dephosphorylation where inactivation/activation is regulated by AMP where high AMP (means low ATP from cholesterol synthesis) activates dephosphorylation?
- hormonal regulation where insulin favors cholesterol synthesis from upregulated HMG CoA and glucagon does the opposite
What is lovastatin and how does it work?
lovastatin is a statin prodrug that is a structural analog of HMGCoA mimicking the intermediate in the reduction by HMG CoA reductase, but as the competitive inhibitor, lovastatin binds several time more tightly than HMG CoA from a higher affinity for the reductase enzyme
How does dietary cholesterol affect the body’s synthesis of cholesterol?
eat too much cholesterol decreases synthesis and vice versa
To what are the rings of cholesterol metabolized in humans?
carbon dioxide and water
How does the sterol nucleus of cholesterol get eliminated from the body?
it is converted to bile acids and bile salts that are secreted in the feces
Detail bile acids.
can be cholic acids with three hydroxyls or chenodeoxycholic acids with two hydroxyls that are in alpha orientations (below plane) so that there are two faces (polar/nonpolar) making them amphiphatic
the carboxyl group has a pKa of 6 so that it isn’t fully ionized at physiological pH which is why acids are most common
How does the bile acid become a bile salt?
through modification in the liver where a glycine or taurine is added by an amide bond
Which is more acidic and fully ionized at physiological pH (salts or acids)?
acids
Which is found in bile (acids or salts)?
ONLY BILE SALTS because they are more effective detergents
How are individuals with genetic deficiencies in the conversion of cholesterol to bile acids treated?
with exogenously supplied chendodeoxycholic acid
What is the order of synthesis in the liver of cholesterol to salts and what is secreted?
cholesterol to bile acids to bile salts
cholesterol with bile salts are secreted
Bile salts that are secreted into the intestines are
efficiently reabsorbed (more than 95%) and reused where the absorption primarily occurs in the ileum and very little is lost and very little is synthesized each day
Bile acid sequestrants such as cholestyramine ___ bile in the gut, ____ their reabsorption, and ____ excretion.
bind
prevent
promote
Cholestyramine is used as treatment of hypercholesterolemia. Explain how it works.
removing bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol (from other tissuse) into that pathway
_____ binds bile acids and increases excretion
cholestyramine
dietary fiber
Name three things degraded by pancreatic enzymes secreted into the duodenum that is necessary for bile to work efficiently.
triacylglycerides
cholesterol esters
phospholipids
The movement of cholesterol from the liver into the bile must be ___.
accompanied by the simultaneous secretion of phospholipids and bile salts
If bile secretion is disrupted or more cholesterol enters the bile than can be solubilized, what can occur?
cholesterol can precipitate in the gall bladder initiating the gallstone disease cholelithiasis
What is the function of bile in the intestines?
Absorption of lipids by intestinal mucosal cells along the brush border of the enterocytes
Explain Zetia (ezetimibe)
an antihyperlipidemic medication to lower cholesterol levels by binding to the Niemann Pick C2 like1 protein to alter the absorption in the GI tract
What is the purpose of fibric acids?
gemfibrozil and fenofibrate treats hyperlipoproteinemias to reduce triglycerides, VLDL, and LDL levels and increase HDL levelsso that the activity of the extrahepatic lipoprotin lipase can regrade chylomicrons, convert VLDL to LDL and convert LDL to HDl
How does niacin reduce cholesterol?
as the precurose for NAD and NADP, it can reduce LDL, triglycerides and HDL levels in a way that is not fully understood
What carries cholesterol bile salts back to the liver through the blood?
albumin
Define a lipid.
a heterogeneous class of naturally occurring organic compounds classified together on the basis of common solubility of insoluble in water and soluble in aprotic organic solvents
What two acid stable enzymes begin the digestion of lipids in the stomach?
lingual lipase and gastric lipase
very important for ppl with pancreatic insufficiency like cystic fibrosis
What is cystic fibrosis?
pancreatic insufficiency where a mutatedchloride channel causes the duct to dry out and not secrete fluids for digestion
Detail lingual lipase.
secreted from the tongue to hydrolyze TAGs with short or medium length fatty acids (this size because of limited time exposure and anything bigger than 12 Cs is too big)
Detail gastric lipase.
secreted by gastric mucosa to degrade short and medium TAGs
Where does emulsification of lipids occur and what purpose does it serve?
occurs in the duodenum to increase the surface area of the hydrophobic parts so digestive enzymes can act at the interface and more effectively turnover
What two processes help emulsification?
detergent properties of bile made in the liver, stored in gallbladder, and secreted into duodenum
peristalsis which moves food through the tract allowing mixing
Detail TAG degradation by pancreatic lipase.
TAGs are large and cannot be taken up easily by mucosal cells so pancreatic lipase removes fatty acids from C1 and C3 such that the primary hydrolysis products are 2 monoacyl glycerol and free fatty acids
pancreatic lipase is in high conc of the pancreatic secretions and without it you get malabsorption of fat usually from cystic fibrosis
Detail cholesterol ester degradation by pancreatic cholesterol esterase.
most dietary cholesterol is in free (non esterified) form but cholester esters are hydrolyzed by this esterase which has enhanced activity in bile
Detail phospholipid degradation by phospholipases.
pancreatic juice is rich in phospholipase A2 which is activated by trypsin in the intestines and requires for bile’s optimum activity such that phospholipase A2 removes one fatty acid from C2 of the phospholipid so that it can be absorbed into the intestines
the C1 fatty acid is removed by lysophospholipase leaving a glycerylphosphoryl base that can be excreted, degraded, or absorbed
What is orlistat?
an inhibitor of pancreatic lipase in order to lose weight and reduce fat digestion and absorption (by 30%) and reduced caloric yield from a diet
It forms a covalent bond in the intestinal lumen with the active site of ser in both gastric ad pancreatic lipase to inhibit the activities
What are the primary products of dietary lipid degradation in the jejunum?
free fatty acids, free cholesterol and 2 monoacylglyerol
all mix with bile salts to form mixed micelles which can be absorbed at the brush border membrane
Do small and medium chain free fatty acids require assistance of mixed micelles for absorption by intestinal mucosa?
no
In what does lipid malabsorption result?
steatorrhea which increased lipids in the feces caused by lipid digestion/absorption problems like cystic fibrosis (poor digestion) or shortened bowel (decreased absorption)
Once micelles are absorbed by enterocytes, what occurs?
they migrate to the ER for synthesis into TAGs and cholesteryl esters to repackage into phsopholipids, unesterified cholesterol and Apo B48
Are TAGs comprised of long chain, medium chain, or short chain fatty acids?
long chain
What are lipids secreted by exocytosis from enterocytes called?
chylomicrons release into the lymphatic vessels and enter the blood via the thoracic duct
Detail the TAG degradation locations and products,
TAGs in chylomicrons are broken down in capillaries of skeletal muscle and adipose tissues (and heart, lung, kidney, and liver) to free fatty acids and glycerol by lipoprotein lipase
What is Type I hyperlipoproteinemia?
familial lipoprotein lipase deficiency that is a rare autosomal recessive disorder resulting from lipoprotein lipase or coenzyme deficiency that leaves massive chylomicronemia dn can only be treated by diet control
What is the fate of free fatty acids?
enter adjacent muscle cells or adipocytes
transported in the blood by albumin until taken up by other cells
adipocytes can reesterify them to produce TAGs for storage
Once TAGs are removed from chylomicrons, what is left?
cholesterol esters, phospholipids, apolipoprotein and some TAGs which bind to receptors on the liver and are endocytosed to recycle cholesterol
What is type III hyperlipoproteinemia?
if the removal of the chylomicron remnants are defective and they accumulate in the plasma
Define apolipoprotein.
proteins that bind lipids such as fat and cholesterol to form lipoproteins and transport the lipids through the lymphatic and circulatory systems. Note apolipoproteins can be referred to as apoproteins
Define lipoprotein
a biochemical assembly that contains both proteins and lipids water-bound to the proteins
Why is LDL bad cholesterol and HDL good cholesterol?
LDL is bad because it delivers the choelsterol to places that can be damaged like other cells
HDL is good because t picks cholesterol up and takes it back to the liver
What is the difference in lipid/protein composition, size, and density of lipoproteins?
chylomicrons have high TAGs and least dense, then we go VLDL, LDL, IDL and HDL which has the most proteins and cholesterol and is most dense
What is the function of lipoproteins?
keep component lipids soluble as they are transported in the plasma and provide efficient mechanism to and from tissue
Detail the general composition of plasma lipoproteins.
neutral lipid core with TAGs, cholesteryl esters surrounded by amphipathic apolipoproteins, phospholipids and nonesterified cholesterol with an apoprotein smeared on the surface
What is the purpose of lipoprotein particles?
provide recognition sites for cell surface receptors
serve as activators or coenzymes for enzymes involved in lipoprotein metabolism
some are essential for structural components and cannot be removed while others are dynamic and freely transferred between particles
What are the main lipoproteins and where are they found?
Apo B48 is on chylomicrons and remnants
Apo E is on all BUT LDL
Apo CII is on chylomicrons, HDL, VLDL, IDL
Apo B100 is on VLDL, IDL, and LDL
How are chylomicrons metabolized?
- assembled in intesinal mucosal cells with TAGs loaded with apo B48 in order to carry TAGs, cholesterol, fat soluble vitamins, and cholesterol esters to peripheral tissue
- modified in plasma so that it receives apo E which is necessary to bind to hepatic receptors and CII which is necessary for lipoprotein lipase from HDL
- degraded TAGs by Lipoprotein lipase
Where does lipoprotein lipase sit?
on capillary walls of most tissues like adipose tissue, cardiac and skeletal muscle bu not the liver
The liver has what enzyme to target HDL?
hepatic lipase
What is lipoprotein lipase activated by?
apo CII
If a lipoprotein lipase or apo CII is deficient, what occurs?
type I hyperlipoproteinemia that causes accumulation of chylomicrons in the plasma
How is lipoprotien lipase regulated?
stimulation is by insulin
adipose tissue has large Km for LPL and heart muscle has a smaller Km (higher affinity so that the heart gets the fat before the other tissues when resources are low)
As chylomicrons circulates ______ of the TAG will be degraded by LPL ____ the size and ____ the density such that CII can be returned to HDL.
more than 90%
decreasing
increasing
What is the purpose of Apo E?
apo E is a recognized apo by liver cells that direct chylomicrons to the liver for recycling
When a chylomicron remnant is endocytosed, the reamining components, _____, are hydrolyzed releasing _____, and recycling the receptor apo E.
apolipoproteins, cholesteryl esters, and etc
amino acids, free cholesterol nd fatty acids
How is VLDL metabolized?
produced in the liver, it is primarily TAGs carrying them to peripheral tissues but also has apo B100 (recognition of cell in peripheral tissues) and receives C and E apos from HDL (which are recycled back once degraded)
It is also degraded by LPL
What do VLDL and HDL exchange when in contact?
TAGs are given from VLDL to HDL in exchange fro cholesteryl esters from HDL to VLDL
How is LDL made form VLDL?
after modification from apo E and CII from HDL, the VLDL is converted to LDL then IDL such that apo E is used to help clear these
What is familial type III hyperlipoproteinemia in regards to apo E?
isoform apo E2 binds poorly to receptors, so homozygotic for this apo E causes deficiency in clearing remnants and IDL.
How does endocytosed cholesterol affect cellular cholesterol homeostasis?
these derived choelsterols can inhibited HMG CoA when in high amounts and decrease the de novo synthesis and reduce LDL receptor synthesis/gene expression and
limit entry of cholesterol into the cell
What happens is cholester isnot used immediately?
it is esterified by acyl CoA:cholesterol acyltransferase (ACAT) and transfered for storage into the cell
How are HDLs metabolized?
because they are heterogeneous family of lipoprotins, the metabolism is not understood but they are secreted into the blood from the liver and intestines
What are the functions of HDL?
HDL is a reservoir of apolipoproteins like apo CII and E
uptake unesterified cholesterol
esterify cholesterol
reverse cholesterol transport (from peripheral to the liver)
Where are chylomicrons assembled?
intestinal mucosal cells from dietary lipids
For protein degradation see the chart you made in the exam 2 review
seriously go through the flow of it, it isn’t difficult.
What are the essential amino acids?
Phenylalanine Valine Tryptophan Threonine Isoleucine Methionine Histidine Arginine Leucine Lysine
How are amino acids driven through the intestinal cells?
through secondary active transport where Na dependent transport co transports AA/Na from high lumen conce to low cell interior conc when Na is driven out and K in by another transporter using ATP
How does aminoterminal amino acids determine the half life of the protein?
arg exists for less than 2 min
val lasts over 20 hours
Whare are the sources of nitrogen for our body?
protein turnover
biosynthesis (of nonessential AAs)
dietary ingested proteins
Where does most proteolysis occur?
in duodenum
What is hartnup disease?
an autosomal recessive disease with a defect in neutral AA transporter on the brush border renal/intestinal epithelium causing malabsoprtion of AA from the lumen and decreased reabsorption from glomerular filter
What are the characteristics of hartnup disease?
hyperaminoaciduria
pellagra like rashes from excreted indolic compounds due to unabsorbed Trp (important for niacin)
What is cystic fibrosis?
a defect in cholirde channels in the pancreatic duct that causes inspissation of pancreatic secretions of exocrine hormones
What is kwashiorkor?
a protein deficient diet despite adequate caloric intake that is very common in third world countries and causes decreased plasma protein conc (spec albumin)
What is cystinuria?
a defect in cys and other basic AAs like arg, lys ornithing transport across brush border that is often asymptomatic but does cause kidney stones in the ureter
Which answer choice contains only essential amino acids?
A. Valine, Arginine, Tyrosine, Proline, Histidine
B. Methionine, Isoleucine, Leucine, Threonine, Tryptophan
C. Proline, Histidine, Arginine, Leucine, Lysine
D. Phenylalanine, Alanine, Leucine, Valine, Tryptophan E. Lysine, Threonine, Tyrosine, Valine, Methionine
B
In which of the following disease processes would you expect to see a neutral hyperaminoaciduria, leading to decreased tryptophan availability for niacin biosynthesis, thus resulting in a pellagra-like rash?
Hartnup disease
Which of the following is closest to the percentage of ammonia molecules that are protonated at physiological pH? 0.01% 0.1% 1% 50% 99%
99%
Which of the following must be removed from any amino acid in order to harness any energy from that amino acid? Side chain R group Hydrogens Alpha-amino group Methyl group Carboxyl group
alpha amino group
Which of the following is a non-essential amino acid:
lysine threonine tyrosine leucine methionine
tyrosine
A child from a refugee camp presents with an unusual rash that suggests malnutrition. However, his parents relate that two siblings have had the same rash and are affected with a disorder called hartnup disease. The physician reads about hartnup disease and decides the rashes are likely to be pellagra, caused by deficiency of niacin. Which of the following deficiencies in hartnup disease would account for the niacin deficiency?
alanine leucine glycine tryptophan isovaline
tryptophan
The transport of amino acids and di- or tripeptides into intestinal epithelial cells can be classified as:
Na+ ion–dependent, secondary active transport
A patient undergoing convalescence is in positive nitrogen balance if:
the amount of nitrogen excreted in the urine, feces and sweat is less than the nitrogen ingested
The impact of cystic fibrosis on protein digestion is that:
mucus blocks the pancreatic duct, leading to poor digestion of dietary protein
Some amino acids can only be made in small quantities in humans and must be supplemented in the diet in children or during repair of injured tissue.
True
Kwashiorkor is a malnutrition disease where amino acid absorption, into the intestinal epithelium, is impaired.
False
The carbon skeletons of many amino acids can be used to replenish the intermediates of the citric acid cycle.
true
What is the difference between a nucleotide and nucleoside?
a nucleotide is the phosphate ester of a nucleoside
