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188 Cards in this Set

  • Front
  • Back
What two things are AAs needed for?
1. Building blocks for proteins
2. building blocks for most essential nitrogen-containing compounds in human cells
From where do we get AAs?
1. from the diet
2. we can make some, but not all, AAs with our bodies (de novo synthesis).
What are 3 causes for altered AA metabolism?
1. Inability to digest proteins
2. Inability to absorb AA from the diet
3. Disorder in protein synthesis/degradation.
Can AAs be stored in the body?
Yes, but only as proteins.
What happens to excess AAs in the body?
1. catabolized to carbon backbones
2. oxideized for energy production
or
3. converted to fuel molecules that are stored.
What toxic substance can be formed from AA catabolism?
Ammonia
How does the body protect itself from ammonia internally?
The body converts ammonia into urea for excretion.
What are the 3 sources of AA that go into the AA pool?
1. Body protein
2. Dietary protein
3. de novo AA synthesis
What compounds can AAs be catabolized into?
1.Glucose and glycogen
2. Ketone bodies, fatty acids, steroids
3. urea, ammonia, uric acid
What are digestive proteases secreted as?
Zymogens
How are zymogens activated by in the digestive tract?
Zymogens are activated by proteolytic cleavage in the digestive tract.
What facilitates the autocleavage of pepsinogen to pepsin?
Gastric HCl
What digests proteins in the stomach?
Pepsin
From where is trypsinogen released?
The pancreas
What cleaves trypsinogen to form trypsin?
Mucosal enteropeptidase.
What is trypsin's role in digestion?
Trypsin cleaves other zymogens to yield their active forms.
Where do pancreatic proteases cleave peptides?
At specific amino acids to yield short peptides and individual amino acids.
Briefly describe the flow of protein digestion beginning with ingestion and ending with transit to the liver.
1. protein --pepsin-->peptides
2. peptides --pancreatic proteases--> oligopeptides, amino acids
3. oligopeptides, amino acids --mucosal aminopeptidases-->
dipeptides, amino acids
4. Absorption through the small intestine
5. transport to the liver
What diseases states can cause deficiency of digestive enzymes?
1. pancreatic disease
2. cystic fibrosis
3. protein malnutrition
What can the prevention of dietary proteins and lipids cause?
steatorrhea (excess fat in the feces)
What is an effective treatment of steatorrhea?
Oral administration of enteric-coated digestive enzymes can effectively treat steatorrhea.
What type of transport allows for the absorption of amino acids and dipeptides?
Carrier-mediated transport.
What trait of an amino acid determines the specific transporter through which the amino acid will enter the mesothelia?
Properties of the AA side chain.
What type of transport is the amino acid/sodium co-transport?
Secondary active transport.
How is a low [Na+] maintained so that AAs can be transported into the cell using the Na+ gradient?
The Na+/K+ ATPase maintains a low intracellular [Na+]
What transport mechanism besides AA/Na+ transport uses the Na+ gradient that we have learned about?
Na+/Glucose symport.
What are neutral dipeptides co-transported with?
H+
Where are neutral dipeptides cleaved into AAs?
In the cytoplasm.
What gradient powers the transport of AAs from the cytoplasm to the blood stream?
the AA concentration gradient (facilitated transport).
Where do transporters in the kidney act on glomular filtrate to resorb AAs?
In the kidney tubules.
From where does intestinal epithelia take up AAs for energy use?
the blood
Is transport of AAs bidirectional?
Yes.
What is the primary consequence of defective AA transporters?
aminoaciduria.
Defects in the transport of what can cause the formation of insoluble precipitates in the kidney?
non-essential AAs
How common is cystinuria, and in what does unabsorbed cysteine result?
1/7000 individuals have cystinuria, and kidney stones result from unabsorbed cysteine.
What is produced in glycinuria that results in kidney stones?
insoluble oxalate due to unabsorbed glycine.
What protein cannot be fully digested in individuals with celiac sprue?
gluten
What type of immune response does an individual with celiac sprue experience after partially digesting gluten?
autoimmune response that damages intestinal mucosa and impairs absorption.
If an individual has impaired transport of an essential AA, what other disease state does that mimic?
an essential AA deficiency (even though the individual is consuming the essential AA)
Which AA cannot be transported effectively in individuals with Hartnup's disease?
Tryptophan
How is Hartnup's disease characterized?
1. Aminoaciduria
2. Niacin deificiency (pellagra)
For what moiety of NAD is tryptophan a precursor?
niacin
How would you treat Cystinuria which would result in:
Urinary cysteine and basic amino acids in the urine, hematuria, urinary hexagonal crystals, and a radioplaque stone in the right kidney?
1. low methionine diet
2. increase fluid intake
3. alkalinize urine
4. cysteine chelating drugs (penicillamine, captopril)
What %age of total body protein is turned over every day?
1 to 2 %
From where do the major contributions of total body protein for turnover come?
1. Intestinal tract
2. RBCs and WBCs
3.Muscle
4. Liver
What %age of the brush border epithelium of the intestine is sloughed off and digested daily?
25%
After how many days are RBCs and WBCs removed from the blood stream for digestion?
~120
During prolonged fasting, why is muscle degraded?
1. to maintain the AA pool
2. to provide substrates for gluconeogenesis in the liver
Why are proteins recycled in the liver?
to remove damaged serum proteins from circulation
What %age of proteins that enter the digestive tract are excreted in feces?
~6% of proteins that enter the digestive tract are excreted in feces.
What is the main serum protein?
Albumin
What pressure does albumin help maintain, and what does that pressure do?
oncotic or colloid osmotic pressure, which holds fluids in the capillaries.
What biomarker is often used to determine general protein health?
serum albumin levels
When are proteins degraded?
Proteins are degraded when they are damaged or no longer needed.
Are proteins and AAs usually excreted?
No, proteins and AAs are usually degraded and recycled.
Of what is AAs (aminoaciduria) a sign?
protein absorption problems
Of what is elevated proteins (microalbuminuria) a sign?
damaged blood vessels to the kidneys, which is a risk factor for kidney failure and a possible symptom of generalized blood vessel damage.
What are diabetics routinely tested for regarding AAs and proteins?
microalbuminuria.
What is the half-life of a protein?
the length of time after synthesis when half of the original molecules remain.
What is degraded in a lysosome?
most MB and organelle proteins, and soluble extracellular proteins are degraded in lysosomes.
Are lysosomal pHs maximally active at low or high pHs?
low pHs
deficiencies in lysosomal enzymes lead to what?
lysosomal storage diseases.
What pathway is repsonsible for the degradation of most cytoplasmic and nuclear proteins?
The ubiquitin-proteosome pathway is responsible for the degradation of most cytoplasmic and nuclear proteins.
Why would apoptosis (programmed cell death) occur?
Apoptosis would occur as part of a developmental program or as a response to severe damage.
Generally, how does apoptosis occur?
1. a cell is systematically broken up into small, MB enclosed packets
2. the packets are phagocytosed and digested by macrophages.
How does apoptosis differ from necrosis?
Apoptosis does not expose intracellular component to the immune system, which could otherwise trigger an autoimmune response.
What happens to undamaged AAs that are released during degradation?
undamaged AAs are recycled.
Is protein degredation in the cytosol regulated?
Yes.
How are proteins that need to be degraded recognized?
They are recognized by built-in or acquired signals.
After a protein is recognized for degradation, what is covalently attatched to the protein?
Ubiquitin (Ub)
What does the activation and transfer of ubiquitin to a protein for degredation require?
ligases and ATP hydrolysis
What targets the protein to the proteosome?
A chain of ubiquitine molecules that is built up on the protein.
What is a proteosome?
A proteosome is a large barrel-shaped protein complex with protein caps at both ends that regulate access to the inside of the barrel, which has multiple proteolytic active sites.
What is the receptor for polyubiquitin on the proteosome?
the cap structure
What sequence of events occurs once the polyubiquitin bound to a protein binds to the proteosome's cap?
1. removal of the ubiquitin chain
2. ATP-dependent unfolding of the protein
3. insertion of the unfolded protein chain into the core of the proteasome.

2.
What happens to peptides and AAs that are released into the proteolytic core?
They are released for recycling or disposal.
What gives a high-degree of control to proteolytic protein degredation?
1. The availability of different ubiquitin ligases that recognize specific degradation signals
2. the multiple energy-dependent steps leading to protein degredation.
Dysfunction in what process might contribute to pathogenesis of Huntington's, Parkinson's, and Alzheimer's?
ubiquitin-mediated protein degradation.
What disease states can produce hypoalbuminemia (low serum protein)?
1. Kwashiorkor
2. Cystic fibrosis
3. disruption in digestive enzymes
4. celiac sprue
5. severe hepatic damage
6. Nephrotic syndrome
How does kwashiorkor lead to hypoalbuminemia?
the diet has sufficient calories but NOT ENOUGH PROTEIN
how does cystic fibrosis lead to hypoalbuminemia?
there is a disruption in digestive enzymes
How does celiac sprue lead to hypoalbuminemia?
there is a defect in amino acid absorption.
How does severe hepatic damage lead to hypoalbuminemia?
There is a disruption in the production of proteins.
How does nephrotic syndome lead to hypoalbuminemia?
There is a nonspecific disorder in which kidneys are damaged and leak large amounts of protein from the blood into the urine.
What disease state occurs with hypoalbuminemia that reduces the body's ability to regulate oncotic pressure and keep fluids in the capillaries?
Peripheral edema.
Cystinuria:
1. substrate
2. transporter
3. pathology
1. Cys, Lys, Arg, Orn
2. Dibasic-cysteine
3. Kidney stones
Dibasic aminoaciduria:
1. substrate
2. transporter
3. pathology
1. Lys, Arg, Orn
2. Dibasic
3. Protein intolerance, hyperammonemia, retardation
Iminoglycinuria:
1. substrate
2. transporter
3. pathology
1. Gly, Pro
2. Glycine, imino acids
3. Benign
Hartnup disease:
1. substrate
2. transporter
3. pathology
1. Branched and aromatic AAs
2. Large, neutral
3. Neutral aminoaciduria, intermittent, symptoms of pellagra
What are the nitrogens of AAs converted to when the AAs are catabolized?
they are converted to ammonia, which is toxic.
What two characteristics of ammonia make it very dangerous for the body?
1. ammonia is a very strong base
2. ammonia can readily cross cell MBs, so it is difficult to remove from the body.
Where does ammonia come from in the body?
1. transamination reactions of all AAs EXCEPT lysine and threonine
2. Purine nucleotide cycle in brain and muscle
3. Threonine and serine undergo dehydration reactions
4. Direct deamination of histidine
5. Deamidation reactions of glutamine and aspargine
6. Gut bacteria metabolism produces nitrogen-->ammonia
What occurs during transamination of AA catabolism?

What important vitamin containing cofactor is required?

What vitamin is needed?
NH3 is transferred from the AA to an alpha-keto acid.

PLP (pyridoxal phosphate)

Vit. B6: pyridoxine.
Where does ammonia (or nitrogen) go in the body?
To the liver
In what AA forms is ammonia transported to the liver from the muscle or peripheral tissues?
1. Alanine (mainly from muscle)
2. Glutamine (mainly from peripheral tissues)
Pyruvate is required for the transamination that forms alanine, where does it come from?
Glycolysis in the muscle.
What enzyme breaks Glutamine down to Glutamate and Ammonia in the liver?
Glutaminase
How many transaminations must occur for an alpha-keto acid to be converted into glutamine?
2
How many deaminations must occur in the liver to turn glutamine back to an alpha-keto acid to release ammonia?
2
Once ammonia is released from alanine and glutamine in the liver by deamination, into what does ammonia get converted? Where does this new molecule go?
Urea, which is excreted through the urine.
How is acetaminophan primarily degraded in the body?

What other way is acetaminophan degraded?
Glucuronidation (90%)

p450 dependent pathway with generation of toxic NAPQI (toxic b/c it reacts with proteins and nucleicAs)
What enzyme is used to convert aspartate to oxaloacete, so that an alpha-keto acid can be converted to glutamate?

What cofactor is used?
Aspartate transaminase (AST)

PLP
How can NAPQI be detoxified?
through GSH (glutathione) conjugation
What is GSH a tripeptide of?
glutamate, glycine, and cysteine
How can you increase glutathione levels?
IV N-acetyl cysteine
How do different organisms remove ammonia?

1. Fish
2. Birds
3. Mammals
1. Excrete ammonia with water
2. Excrete Uric Acid
3. Excrete Uria (non-toxic, soluble)
What are the substrates of the urea cycle?
(HCO3-) and NH4+
What are the substrates of the urea cycle, and what are the enzymes and products of the subsequent reactions?

5 steps
Substrates: HCO3- + NH4+

1. Carbaoyl P-synthetase I (CPS I) -->Carbamoyl Phosphate

2. Carbamoyl (P) + Ornithine --Ornithine Transcarbamoylase (OTC)--> Citruline

3. Citruline + Aspartate --Argininosuccinate Synthetase (ASS)-->Argininosuccinate

4. Argininosuccinate --Argininosuccinate Lyase (ASL) -->Fumarate + Arginine

5. Arginine --Arginase--> Ornithine + UREA
mneumonic for remembering the urea cycle enzymes
CPS I --> OTC
ASS -->ASL
ARGINase
Which reaction(s) of the urea cycle occur in the mitochondria?
1. OTC: carbamoyl (P) + ornithine = citrulline
Which reaction(s) of the urea cycle occur in the cytosol?
2. ASS: citrulline + aspartate = argininosuccinate
3. ASL: argininosuccinate = fumarate + arginine
4. Arginase: arginine = urea + ornithine
Which reactants of the urea cycle are transported between the mitochondria and the cytosol?
1. citrulline
2. ornithine
What is the amount of urea produced by the urea cycle directly proportional to?
The amount of AA nitrogen that undergoes catabolism
When will urea production increase?
Urea production increases under:
1. the early stages of starvation
2. in response to injury, trauma, and infection (hypercatabolic states)
In a hypercatabolic state, will ammonia levels increase or decrease?
Neither, ammonia levels will remain fairly constant
Does ammonia regulate the urea cycle?
No.
What is the main regulated enzyme in the urea cycle?

What regulates that enzyme? How is it regulated?
CPS I
(HCO3-) + NH4+ = carbamoyl (P)

CPS I is allosterically regulated by N-acetyl glytamate (NAG)
What effects do arginine levels have on the liver?
1. arginine stimulates the synthesis of NAG, which allosterically regulates CPS I.

2. arginine increases production of ornithine via the arginase reaction.
What are 2 enzymes are common clinical markers for liver function?
Alanine transaminase (ALT)

Aspartate transaminase (AST)
what reaction does alanine transaminase (ALT) catalyze?
alanine + alpha ketogluterate = pyruvate + glutamate
Where does pyruvate --> oxaloacetate?
In the mitochondria
What reaction does aspartate transaminase catalyze?
Oxaloacetate + glutamate = aspartate + alphaketogluterate
What two processes benefit from aspartate's transfer from the mitochondria to the cytosol?
1. urea synthesis

2. gluconeogenesis (carbon skeletons and reducing equivalents)
Which enzymes of the urea cycle can exhibit reduced efficiency due to genetic defects?
All 5 enzymes
What 3 symptoms present with genetic defects of urea cycle enzymes?
1. hyperammonemia (ammonia cannot be converted to the less-toxic urea)
2. encephalopathy (ammonia is a neurotoxin)
3. alkalosis:pH > 7.45 (can be caused by excessive vomitting)
How many times must ammonia levels increase to be toxic to the nervous system?
5 to 10 times.
Why can NH4+ block K+ channels in neurons?
NH4+ has the same ionic radius of K+
How can the inability to convert ammonia to urea cause osmolarity changes?
Accumulation of glutamine
How does hyperammonemia affect NT synthesis and OxPhos?
Inhibits NT synthesis and impairs OxPhos.
Name the fat soluble vitamins
A, D, E, K

You are a fat ADEK
What forms can Vitamin A be found i?
Retinal, Retinol, Retinoic acid, and Beta-Carotene
Vitamin A as a Tx for?
night blindness caused by Vit A deficiency

promote a healthy immune system

growth and development of cells

keratinolytic skin
What does Vitamin A deficiency cayse?
Xerophtalmia: dryness of the conjunctiva and cornea of the eye

Long-term deficiency: chronic eye ulceration and blindness = night blindness
How is a Vit A supplement added to food?
The gene to make Vit A has been added to rice.
What does an excess of Vit a cause?
Pseudotumor Cerebri (cells try to absorb so much Vit A that they expand, terrible headaches)

Teratogenesis (abnormal embryonic development).
Which Vitamin has the lowest therapeutic range?
Vitamin A
What form of Vitamin A is used to treat acne and how does it work?
All-trans-retinoic acid: keratolytic.

Helps stop the overgrowth of keratinocytes (skin fibroblsts) so that sebaceous glands will not be closed off to prevent release of sebum.
What is a dangerous side-effect of accutane?
Accutane (all-trans-retinoic acid) is a CNS depressant-->adolescent suicide.
Where is Vitamin D made?
It is a steroid made in the skin.
What is the function of Vitamin D?
Vitamin D regulates Ca++ and PO4- metabolism.

1, 25-dihydroxycholecalciferol made from ergosterol by UV irradiation of the skin interacts with nuclear DNA to enhance transcription of Ca++ binding proteins in the gut and kidney.
Where is the only place in the body that the 1-hydroxylation of ergosterol to yield Vitamin D can take place?
In the Kidney, so renal failure can lead to Vitamin D Deficiency.
What will an overdosage of Vitamin D cause?
Hypercalcemia -->fatigue
What manifests from Vitamin D deficiency?
Rickets and Vitamin-D deficient rickets
What is rickets?
It is the softening or weakening of bone due to deficiencies in Vitamin D, Ca++, and/or PO4-
Where do we get Vitamin K?
Vitamin K is made by gut bacteria (intestinal flora)

But all infants receive an injection of Vitamin K as menadione at birth.
What is is Vitamin K used for in the body?
Vitamin K is a cofactor for gamma-glutamylcarboxylase in clotting factors II, VII, IX, and X, and anti-clotting proteins C an S.

In short, Vitamin K is a cofactor for the regulation of blood clotting.
Why do newborns need an injection of Vitamin K?
To prevent bleeding from the recently cut umbilical chord.
What inhibits Vitamin K recycling?
Warfarin (anticoagulant)

Antibiotics: which kills the bacteria that synthesize Vitamin K.
Is Vitamin E required?
Requirement of Vitamin E depends on the amount of polyunsaturated fatty acids that are consumed.
What is the primary population that experiences Vitamin E deficiency?
Premature infants
Is Vitamin E the most or least toxic fat soluble vitamin?
Vitamin E is the least toxic fat soluble vitamin.
What is Vitamin C used for in the body?
1. Vitamin C reduces glutathione

2. Vitamin C prevents scurvy.

3. Vitamin C is involved in the oxidation of steroids to bile acids (the only exit for cholesterol from the body)

4. Vitamin C is involved in the hydroxylation of collagen lysines.
What is the amount of Vitamin C stored in the body when the body is healthy?
1500 mg
How much vitamin C is used in the body per day?
when the Vitamin C pool = 1500 mg, 45 mg/day are used.

when the Vitamin C pool ~300 mg, 9 mg/day are used.
About how many days will the Vitamin C pool last in a human body?
about 30 days, because 8 to 10 mg/day must be lost.
Where is Vitamin C stored in the body?
The Adrenal gland and leukocytes store vitamin C.
Why might we not contain the entire gene, for gulonolacetone oxidase, to produce endogenous vitamin C?
1. Vitamin C is stored in the adrenal and is used in the hydroxylation of a steroid to make cortisol from cholesterol.
2. Under periods of stress, cortisol is realeased to stimulate gluconeogenesis from glycogen and proteins.

There is a limited amount of Vitamin C stored in the body, and we do not make it on our own, because during any stress, vitamin C aids in the production of cortisol, which will be released and cause the digestions of body proteins and glycogen stores for energy usage. Limiting the amount of Vitamin C in the body limits cortisol productions and protects the body's proteins from excessive degradation.
What is Vitamin B1 called?
Vitamin B1 = Thiamine.
What is Thiamine used for?
Thiamine (B1) prevents beri-beri.

Thiamine is a cofactor for alpha-keto acid dehydrogenases in metabolism of branch chain AA, pyruvate, and alpha ketogluterate.
What can a deficiency in Thiamine(B1) cause?
Thiamine deficiency can cause:
1. paralysis of eye movements, confusion, ataxia (Wernicke-Korsakoff encephalopathy)
What are some Thiamine(B1) responsive diseases?
1. thiamine (B6) responsive lactic acidosis

2.thiamine (B6) responsive maple syrup urine disease

3. Subacute necrotizing encephalopathy
What is B2 aka?
Vitamin B2 is aka Riboflavin
What is Riboflavin (B2) important for?
1. Riboflavin is part of FAD

2. Complex II of ETC

3. Target of thyroid hormone: Thyroxin, which controls the rate of E production in the whole cell.

4. aka Succinate dehydrogenase

5. Fatty Acid Oxidation (used to Tx MCAD Deficiency)
What disorders is Riboflavin (B2) a Tx for?
1. Medium Chain Acyl CoA Dehydrogenase Decifiency (MCAD Deficiency)
2. Glutaric Acidemia, Type II
What is Vitamin B3 aka?
Vitamin B3 is aka Nicotinamide
What important electron acceptor is Vitamin B3 (Nicotinamide) a part of?
NAD+, the niacin part.
What is caused by Niacin (B3) deficiency?
Pellagra

4D's: Dementia, Dermititis, Diarrhea, Death
What is Niacin (B3) used to treat?
Niacin (B3) is used to treat hypertriglyeridemia.
What AA is niacin(B3) made from?
Tryptophan
What AA inhibits synthesis of Niacin(B3) from Tryptophan?
Leucine
What regulates Niacin(B3) synthesis from Tryptophan? What is made if the regulating factor is not present in sufficient quantities?
NADH levels

Nicotinic Acid (the acid form of B3, not the amide)
How can Niacin (B3) prevent fatty acid release from fat stores?
timed-release Niacin (Niaspan)

When NADH levels are low, nicotinic acid is made. It inhibits hormone sensitive lipase. It is just acidic enough to trick hormone sensitive lipase into thinking that it is an acid, so the hormone sensitive lipase will not increase the amount of acid by releasing fatty acids.
What is vitamin B6 aka?
Pyridoxine, pyridoxal phosphate
Where is the biggest mass of B6 found?
The biggest mass of pyridoxine is found attached to glycogen phospharylase.
What are the important functions of Pyridoxine (B6)?
1. cofact in NT synthesis (catecholamines)
2. cofactor in transaminase reactions
3. Cofactor in glycogenolysis
4. cofactor in steroidogenesis
What is Pyridoxine (B6) used to Tx?
PMS!!!!
Neonatal seizures
Enhancement of dream recall

-seizures of newborn babies
What is the active form of folic acid?
Tetrahydrofolate
What is caused by folate deficiency?
macrocytosis: cell enlargement (esp RBCs) which leads to macrocytotic anemia.
What is Folate a cofactor of?
1. Thymine(DNA) synthesis from Uracil(RNA)

2. The Methionine Cycle
What is Vitamin B9 aka?
Folate! Folic Acid!
What is the folate trap?
A deficiency in Cyanocobalamin (Vit B12) will prevent the de-methylation of folate (B9), because Cyanocobalamin receives the methyl group from methylene-THF to yield THF which can be used as a cofactor for Thymine synthesis and the Methionine cycle. The Folate, THF, is "trapped" in its methylated form. This condition mimics folate deficiency.
What is Vitamin B12 aka?
Cyanocobalamin
What occurs due to a deficiency in cyanocobalamin?
Pernicious anemia, macrocytosis.
What is needed to absorb cyanocobalamin (B12)?
Intrinsic Factor from parietal cells of the stomach. Anything that irritates the lining of the stomach can cause Vitamin B12 deficiency.
What is cyanocobalamin (B12) a cofactor for?
1. methylation of propionate to succinate via methylmalonate.
Where is Vitamin B12 found?
only in animal products.
What is Vitamin B7 aka?
Biotin
What is biotin(B7) a cofactor for?
1. carboxylation and carbon fixation in humans.
2. anapleurotic rxns.
3. coenzyme for pyruvate carboxylase which makes oxaloacetate
4. binds tightly to avidin.