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Biochemistry
Nucleotide/Amino Acid Metabolism
88
Medical
Professional
07/21/2010

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Cards

Term
ATP roles
Definition
**most abundant of the nucleotides in the body

-Biosynthesis
-Movement
-Ion Pumping
-Present in Cofactors-->facilitate metabolic pathways
Term
GTP roles
Definition
G-protein signaling
Term
CTP Roles
Definition
CTP-lipid precursors leading to synthesis of phospholipids & sphingolipids
Term
UTP Roles
Definition
-UDP sugars leading to formation of polysaccharides
Term
RNA v. DNA
Definition
RNA: ribonucleotides (ATP, GTP, CTP, UTP)
-ribose sugar

DNA: deoxyribonucleotides (dATP, dGTP, dCTP, dTTP)
-deoxyribose sugar (absence of a hydroxyl group on the 2' group compared to ribose)
Term
Nucleotide Components
Definition
-Phosphate
-Sugar (Ribose or Deoxyribose)
-Nitrogenous Base
Term
Purines
Definition
*made of two rings

-Adenine
-Guanine
-Xanthine
-Hypoxanthine (X & HX are intermediates in production and degradation of major nucleotides)
-Uric Acid (final product of protein degradation)
Term
Pyrimidines
Definition
*One ring

-Cytosine
-Uracil
-Thymine
Term
Purine Nomenclature
Definition
**all end in -sine, except Cytosine

Ribonucleoside--Adenosine [AMP], Guanosine [GMP], Xanthine [XMP], Inosine [IMP](base & ribose= -side)

Deoxyribonucleoside: Deoxyadenosine [dAMP] & Deoxyguanosine [dGMP]
Term
Pyrimidine Nomenclature
Definition
**all end with -dine

Ribonucleoside: Uridine [UMP], Cytidine [CTP], Oritidine [OMP]

Doexyribonucleoside: Deoxyuridine [dUMP] (only used as a precursoe for dTMP synthesis in DNA-not incorporated into DNA), Deoxycytidine [dCMP], Deoxythymidine [dTMP]
Term
Nucleotide
Definition
-phosphorylated nucleoside (base + sugar + phosphate)
-derivatives required in polysaccharide synthesis
Term
De Novo v. Salvage Pathway
Definition
De Novo: for purine and pyrimidines, pathways are conserved among all cell types
-purine & pyrimidine nucleotide synthesis is fundamentally different
-more important is faster growing cells (e.g. liver & kidney)
*using simple molecular precursors

Salvage: pathways are conserved but the uses vary widely among different cell types
-purine & pyrimidine nucleotide synthesis is fundamentally different
-more important in slower growing cells
*using nucleosides from degraded nucleic acids
--allows for different cells to produce nucleotides according to its specific needs--
Term
De Novo Purine Synthesis
Definition
-purine components are constructed in a series of steps from relatively simple metabolites

Ribose-5-phosphate (from the Hexose Monophosphate shunt) --1--> PRPP --2--> beta-5-Phosphoribosylamine

1.highly regulated step; catalyzed by Ribose-5-phosphate pyrophosphokinase---uses 2 ATP--adss two phosphates

2. highly regulated step; catalyzed by Aminophosphoribosyl Transferase (first committed step)---requires Glutamine & water

PRPP=phosphoribose pyrophosphate (can be used for salvage pathway)

*Aspartate, Glutamine, and Glycine supply all of the N and some C. Bicarbonate ion and Formyl-THF (carrier that donates 1 carbon) supply the rest of carbons.

-building up happens in the same place
Term
IMP (Inosine Monophosphate)
Definition
ATP<--2--ADP<--1--AMP<--Adenylosuccinate<--IMP-->XMP-->GMP--1-->GDP--2-->GTP

1-these reactions require a distinct kinase to catalyze the addition of the first phosphate to NMP and form the NDP
2- nucleoside phosphate kinase: the only enzyme that phosphorylates diphosphates to triphosphates
Term
NDP Kinase
Definition
-can extract the phosphate from any NTP and transfer it to the substrate NDP
-catalyze ATP conversion to ADP & NTP-P
-produced by the reaction: NDP + NDP Kinase-P to yield NTP & NDP kinase
Term
Ribose v. Deoxyribose
Definition
-absence of a hydroxyl group on the 2' group in deoxyribose
Term
RNA synthesis Energy Source
Definition
NMP-->NDP-->NTP
*energy stored in phosphate ester bonds used to drive DNA and RNA synthesis
Term
PRPP
Definition
-activated form of ribose-5-phosphate
-used in both purine & pyrimidine biosynthesis but in different ways


*PRPP- activates amidophosphoriribosyl transferase and thus its consumption in the de novo pathway
Term
Salvage Pathway Purine Synthesis
Definition
-purine nucleotide components from dietary sources and degraded cellular nucleic acids
-base-->Nucleoside[Base-Ribose] (catalyzed by nucleoside phosphorylase & Ribose-P)
-Nucleoside-->NMP[Base-Ribose-Phosphate] (catalyzed by Nucleoside Kinases & Phosphate)
-Base-->NMP [Base-ribose-phosphate] (catalyzed by Phosphoribosyltrasnferases)

*certain expression at a needed time can take place

-similar to pyrimidine salvage pathways
Term
Regulation of Purine Nucleotide De Novo Synthesis
Definition
Feedback Inhibition of PRPP conversion to beta-5- Phosphoribosylamine: ATP, AMP, ADP, GMP, GDP, GTP

Activation of PRPP conversion to beta-5-phosphoribosylamine: PRPP

Inhibition of Ribose-5-phosphate conversion to PRPP: ADP & GDP

Inhibition of conversion of IMP to Adenylsuccinate: AMP

Inhibition of conversion of IMP to XMP: GMP

GTP: used as an energy source for production of adenylsuccinate

ATP: used as an E source for production of GMP
Term
Salvage Transport
Definition
Diet supplies NMP--{Dephosphorylation}--> Nucleoside in the blood--{Kinase}--> at Destination converted to NMP
Term
AMP v. IMP relationship
Definition
AMP--(AMP deaminase)-->IMP

*GDP-discourages conversion to G
*ATP-activates AMP deaminase; encourages conversion to G
Term
GMP v. IMP relationship
Definition
GMP--GMP reductase-->IMP

*GTP-encourage conversion to A
Term
Deficiencies in PRT
Definition
PRT-phosphoribosyl transferases
*APRT/HGRT

-PRPP accumulates and is broken down into uric acid
-activates the de novo pathway if PRPP is in excess
Term
Lesch Nyhan Syndrome
Definition
-only present in males
-X-linked recessive
-due to HGRT deficiency (lack of salvage pathway activity)
*causes accumulation of PRPP, stimulating de novo purine nucleotide synthesis and excess purines are degraded into uric acid

Symptoms: mental retardation, self-mutilation (head smashing-biting of hands/fingers), and aggression
*wrist restraints are necessary
Term
Pyrimidine Nucleotide de novo Pathway
Definition
simple precursor molecules---->Orotate (base)--PRPP-->OMP-->UMP--1-->UDP--2-->UTP-->CTP

*distinguished by Orotate formation independent of any sugar cmpd; then PRPP activates it
*3 of the ring carbons and all N are derived from glutamine & aspartate; additional ring carbon is acquired from bicarbonate

-all pyrimidine nucleotides are derived from UMP

1-uridine monophosphate kinase produces UDP from UMP
2-nucleoside diphosphate kinase produces UTP fromUDP
Term
Modular v. 'Stick-built'
Definition
*for de novo

pyrimidine synthesis: put together in a separate place away from its utilization
*size is restricted*
-base is put independent of sugar-

purine synthesis: built upon a specific ribose molecule; same place as utilization
Term
Regulation of Pyrimidine Nucleotide de novo pathway
Definition
EUKARYOTES-first step is catalyzed by CPS II (1st committed step) [carbamoyl phosphate synthetase II)

PROKARYOTES-only has CPS, producing carbamoyl phosphate used in pyrimidine synthesis and the urea cycle
Second step catalyzed by ATCase (aspartate transcarbamoylase) is the first committed step

for both prokaryotes and eukaryotes, the 1st committed step is regulated

-Inhibition on CPS II or CPS catalyzed reaction: UDP & UTP ---in eukaryotes---
-Inhibition of ATCase: UTP & CTP ---in prokaryotes---

-abundance of the purine nucleotide ATP stimulates the pyrimidine pathway and provides a mechanism for establishing a purine-pyrimidine balance
Term
UMP Synthase
Definition
-has two activities; dual-function protein

** Orotic Aciduria: 1. decrease level of protein--cause decrease in both enzymes, OMP decarboxylase and OPRT
2. decrease in OPRT activity
3. decrease in OMP decarboxylase activity

2&3 will cause a change in OMP & UMP levels
Term
Nucleotide Synthesis & cell cycle
Definition
-deoxyribonucleotides is necessary only in S phase
*for purine nucleotide synthesis, the levels of amidophosphoribosyl transferase and IMP dehydrogenase are elevated during late G1 and S phae
-in pyrimidine synthesis, enzymes such as CPS II are also at high levels

*increased abundance of regulated enzymes for purine/pyrimidine synthesis is related to proportion of cells in tissues actively growing and dividing
Term
IMP-DH
Definition
catalyzes conversion of IMP to XMP
Term
Nucleoside Phoshorylases
Definition
-convert free bases to nucleosides by addition of ribose
-enzymes are named by reverse reaction that uses a phosphate to cleave the glycosidic bond between base and sugar
Term
Nucleoside kinases
Definition
-add phosphate group to a nucleoside to produce the corresponding molecule
Term
Phosphoribosyl Transferases
Definition
-convert bases directly into nucleotides by addition of a ribose-phosphate

-use PRPP as source of ribose-phosphate

-specific to a specific nucleotide
Term
Parasites & salvage pathway
Definition
-Primarily infectious pathways lack the de novo pathway and rely on the salvage pathways to recycle nucleotide components from the host organism
Term
Why are only a small fraction of mutations seen in organims?
Definition
-lack of any particular enzyme's activity or partial lacking of enzyme's activity is lethal in utero
Term
CTP & de novo pathway
Definition
-only formed at the NTP level by amination of UTP
Term
Orotic Aciduria
Definition
-genetic disease causing orotic acid excretion
-Symptoms: anemia, retarded growth, and person may not live to maturity

treatment: uridine ingestion, which is converted to UMP
Actions:
1. Allows for normal synthesis of pyrimidine nucleotides
2. The resulting UDP & UTP discourage excess accumulation of orotic acid via the feedback inhibition of CPS II
Term
Enzymes & Tumor Development
Definition
-profile of relative enzyme levels can serve as hallmark of states of tumor development
-IMP dehydrogenase is considered a progression-linked enzyme because alterations in its level correlate with tumor growth rate
Term
Ribonucleoside reductase
Definition
conversion of nucleotide diphosphate to nucleotide triphosphate (for all 4 nucleotides--A,G,C, U)

--Heterotetramer: two alpha (activity) and two beta (regulatory) sites: conversions take place at the interface between alpha and beta

*always acts at diphosphate level always

Allosteric Sites: Activity & Specificity Site
Term
Allosteric sites of Ribonucleotide Reductase
Definition
Activity Site: high levels of ATP activate and high levels of dATP inhibit

Specificity Site: particular nucleotides control reduction of particular substrates
**creates balance of deoxyribonucleotides

too much= misincorporation
Specificity Site:
Term
Regulation of Ribonucleotide Reductase
Definition
*dTTP
-activate conversion of GDP to dGDP
-inhibits conversion of CDP to dCDP and UDP to dUDP

*dGTP
-activates conversion of ADP to dADP
-inhibits conversion of GDP to dGDP, UDP to cUDP, and CDP to dCDP

*dATP
-inhibits conversion of ADP to dADP, GDP to dGDP, UDP to cUDP, and CDP to dCDP
Term
Uracil appearance in DNA
Definition
-misincorporation (U is incorporated rather than T)
*seen in new DNA (replaced with T)
-deamination of cytosine (occur after established DNA, replace the U with a C
Term
Methylene THF
Definition
-deliver methyl group (Thymidilate synthae) rxn to form DHF (oxidized)
-serves as reducing agent (aldehyde to alcohol)
Term
Conversion of dUTP to dTTP
Definition
dUTP---dUTPase--->dUMP + P---Thymidilate synthase--->dTMP---dTMP Kinase--->dTDP---NDP kinase--->dTTP
Term
Folate Cofactors
Definition
-purpose: deliver 1-c units
-Formaldehyde: reduce C as its being delivered in the rxn
-needs DHFR to recharge (convert DHF back to N,N-methylene-THF
Term
Folate Cofactor Recharging Cycle
Definition
N,N-methylene-THF---Thymidilate synthase (using dUMP to form dTMP)--->DHF---DHFR (using NADPH to form NADP+)---> THF---Serine Hydroxymethyl Transferase (using serine to form glycine)--->N,N-methylene
Term
Diversity in rates of cells division
Definition
-developing tumor divides as fast as intestinal epithelium and divides faster than basal epidermis, liver, and brain cells
Term
Mechanisms of Thymidilate Synthesis Regulation
Definition
1. inhibition of Thymidilate synthesis
Fluotouracil(suicide inhibitor) takes place of uracil to form FdUMP [recognized as a substrate by the enzyme]
*fluorine can not be eliminated to add a CH3 group/enzyme is 'stuck'

2. inhibition of DHFR
*DHF, Methotrexate, Aminopterin (last two are DHF analogs)---all three bind as well as each other (competitive inhibitors--->prevent the synthesis of dTMP and replenishing of N,N-methylene-THF)

3. inhibition of dTMP synthesis & thus DNA synthesis
*FdUMP inhibits Thymidilate synthase and Methotrexate Aminopterin inhibits DHFR
Term
Advantage of Uric Acid
Definition
-insoluble in water (good for terrestrial animals)--->does not necessitate water
-an antioxidant: counteract ROS---reactive oxygen species---increase ROS = decrease in longevity
Term
Chemotherapy side effects
Definition
-affects intestinal epithelium, bone marrow (blood tissue), and general weakness (loss of hair, etc)
-rounds of chemotherapy are designed to kill significant numbers of tumor cells while leaving a large enough population of normal cells to carry on sufficient physiological function
Term
Purine/Pyrimidine Degradation Products
Definition
Purine: uric acid
Pyrimidine: FA precursors, Amino acid, CAC intermediates
Term
Inhibition of Xanthine Oxidase
Definition
e.g. ALLopurinol (hypoxanthine analog)
-outcompetes hypoxanthine for binding site---hydroxylation occurs and the result compound, alloxanthine has an even higher affinity to XO and blocks production of uric acid

Hypoxanthine and Xanthine tend to accumulate-can be ridden off easier b/c they are water-soluble by the kidneys
Term
Cells requiring deoxynucleotides
Definition
-all active cells require small quantities of deoxynucleotides to synthesize a new copy of DNA
-ATP:ADP ratio: higher the greater the activation of deoxynucleotide synthesis
Term
Lethal Synthesis
Definition
Fluorouracil--->FdUMP

*this mechanism can kill actively growing cells
Term
DNA polymerase & inhibition of DNA synthesis
Definition
-nucleotide analogs can be used to inhibit DNA synthesis by causing chain termination
-b/c of lack of 3'-OH group on the sugar ring, preventing attachment of next nucleotide
Term
Purpose of Nucleotide Degradation
Definition
1. N.A. & nucleotides in diet are broken down to nucleosides-P and Ribose + Base
1. Catabolism of 'old' N.A.s and nucleotides

occurs to eiliminate waste and to create UA-an antioxidant and formation energy precursors
Term
Purine Catabolism
Definition
-Purine Nucleotides are degraded to Uric Acid
-Nucleotidases: remove phosphate
-Purine Nucleoside phosphorylase: remove ribose
Term
Deficiency in Adenosine Deaminase
Definition
Adenosine deaminase: responsible for conversion of adenosine (adenine + base) to inosine
-deficiency causes increased accumulation of adenosine and deoxyadenosine
-both are then phosphorylated by adenosine kinase to yield AMP and dAMP
-high levels of AMP-not problematic
-high levels of dAMP-->dATP=very problematic (inhibits RR activity & thus reduction of ALL NDPs--DNA synthesis is blocked)

Problem?
1. Fast cell division does not occur- B & T cells proliferate upon infection (proficient at phosphorylation of deoxyadenosine
1. High Adenosine kinase-->SCID (trouble defending against pathogens; tx: bone marrow transplant)
Term
Gout
Definition
-hyperurecemia: causes formation of sodium urate crystals (can potentially block small blood vessels)
*affects joints of the extremities, causing pronounced inflammation and arthritis

May be due to three metabolic problems:
1. hyperurecemia: lack of sensitivity to metabolites that normally feedback inhibit the initial steps of purine de novo synthesis
2. PRPP synthesis in some instances is overly active, similarly causing excessive synthesis of purine nucleotides
3. Deficiency in HGPRT activity results in reduced salvage of guanine, accumulation of PRPP and thus overproduction of purines and subsequent degradation to uric acid
Term
Amino Acids
Definition
-building blocks of proteins
-can form hormones, heme, neurotransmitters, proteins, and nucleotides
*when broken down:
N-Urea Cycle, excretion
C-used for gluconeogenesis, CAC, and FAs
Term
Nitrogen Supply
Definition
-transient
-amino acids are not stored as fuel
-acquisition and N-releasing breakdown of AAs largely controls the organism's overall supply of Nitrogen
Term
How do organisms obtain Nitrogen?
Definition
Air is majority Nitrogen---Nitrogen fixation by specific bcteria--->ammonia is deposited in the soil---plant absorption--->Plants then supply other organisms with organic nitrogen mainly in form of protein
Term
Nitrogen fixation
Definition
catalyzed by nitrogenase
*sensitive to oxygen--energy is expended to create a low-oxygen environment
Term
Nitrogen Balance
Definition
overall amount of N being used in synthesis of biomolecules is equal to the amount being released by degradation of biomolecules
Term
Negative Nitrogen Balance
Definition
-more nitrogen is excreted than is ingested
-increase in rate of protein degradation
-occurs due to general starvation, dietary deficiency of an essential amino acid, advanced aging
Term
Positive Nitrogen Balance
Definition
-rate of protein synthesis exceeds the rate of protein degradation
-occurs during growth in children, pregnancy, recovering from starvation or trauma
Term
Degradation of Proteins in the body
Definition
-proteins cleaved by variety of proteases
-acidic environment in stomach allows pepsinogen-->pepsin, to denature proteins
Pepsin: hydrolyzes peptide bonds connecting amino acids in polypeptides

-Duodenum: release of bicarbonate neutralizes the pH and zymogens of pancreatic proteases are released
*lining of small intestine cells release enteropeptidase, which activates trypsinogen-->trypsin, which activates the remaining zymogens

*Single amino acids travel to liver and then enter circulation via hepatic portal vein
Term
Protein Turnover
Definition
-proteolysis takes place under conditions of energy need
-some proteins may be degraded to produce energy when necessary
-proteins with abnormal structures are recognized and destroyed
Term
Lysozyme
Definition
-site of general protein degradation
-carries protein degradation via fusion with vesicles (internal) and endocytosis (external)
-maintain a low pH
-has its own complements of proteases
Term
Proteasome
Definition
-control proteins key in regulatory processes in the cells' physiological processes
-proteins are targeted by enzymatic attachment of ubiquitin molecules
-N-terminus AA as well as phosphorylation render proteins susceptible to ubiquitination & subsequent destuction
Term
Huntington Disease
Definition
-neuropathology is localized to corpus striatum b/c binding protein Rhes is specifically found in CS and binds to mHtt to cause sumoylation and eventually cytotoxic effects
Term
Biosynthesis of Nonessential Amino Acids
Definition
Essential; not produced in the body at a sufficient level (must be ingested)

Nonessential: produced in the body, but cysteine is produced from methionine (an essential AA) and Tyrosine from phenylalanine (an essential AA)
Term
Transaminase
Definition
-catalyzes exchanged of an alpha-amino group to a keto oxygen of the alpha-keto acid (Transamination)

OAA--->Aspartate
Pyruvate-->Alanine
alpha-ketoglutarate--->glutamate

-various kinds in the human cells, allowing for selection of amino acids that happen to be in excess at any particular time or in any particular cell type to be sourced of amino groups in the product
Term
Transamination
Definition
-OAA + Glutamate--->aspartate + alpha-ketoglutarate
Term
PLP
Definition
pyridoxal-5'-phosphate: derived from pyridoxine, vitamin B6
-acts as a carrier of an amino group during transamination

compromised AA synthesis---> B6 deficiency

lack of TA activity=lack of neuronal function in extremities
Term
Glutamate
Definition
-only amino acid whose alpha-amino group can be formed by the direct incorporation of nitrogen from ammonia
--formation catalyzed by glutamate dehydrogenase plus ammonium and NADPH
Term
How are Asparagine & Glutamine formed?
Definition
Asparagine: TA catalyzes OAA--->Aspartate; Aspartate Synthetase with Glutamine and ATP catalyzes Aspartate-->Asparagine

Glutamine:
TA catalyzes alpha-ketoglutarate-->Glutamate

Glutamine Synthetase with ammonia and ATP catalyzes glutamate-->glutamine
*only rxn in which N from ammonia is directly incorporated into an amino acid


Glutamine:
Term
PKU
Definition
phenylketonuria
-normally, phenylalanine used to create tyrosine using phenylalanine hydroxylase
-in PKU, there is loss of phenylalanine hydroxylase activity and phenylalanine is converted to phenylpyruvate (which comes out in the urine)

symptoms: affects neural development, causing mental retardation

treatment:limit Phe in diet, supply more tyrosine
Term
Oxidative Deamination
Definition
e.g. deamination of glutamate by glutamate dehydrogenase (liberates ammonia) produces alpha-ketoglutarate

-glutamate: funnel for flow of nitrogen from amino acids to ammonia

GDH: regulated by purine nucleotides
high ATP: inhibition
high ADP: activation
Term
Seven roles of glutamate
Definition
1. Amino donor:important for transamination
2. glutamine used to form glutamate
3. inorganic N in form of NH3 is used to form alpha-amino
4.a switch to catabolism
5. glutamate can be degraded
6. regulation of glutamate dehydrogenase: tied to ATP/ADP ratio abundance
7.interconversion of alpha-ketoglutarate and glutamate
Term
Urea Cycle
Definition
-N used to make urea are taken indirectly from glutamate and aspartate in a cyclic metabolic pathway
-Before, NH3 must be activated in the form of carbamoyl phosphate
-ammonium and bicarbonate --->carbamoyl phosphate [[catalyzed by Carbamoyl phosphate synthetase I]]
*requires 2 ATP
-such step serves as the committed and rate-limiting step
*N-rich urea is excreted in the urine

ornithine + carbamoyl phosphate--->citrulline
citrulline + aspartate--->arginosuccinate
arginosuccinate --->arginine + fumarate (enters CAC where it is converted to OAA)
arginine + water--->ornithine (and urea is released)
Term
OAA
Definition
fumarate-->malate-->NADH + oxaloacetate
-can undergo transamination to regenerate aspartate, enter gluconeogenesis or remain as an intermediate of the CAC
Term
Hyperammonemia
Definition
can cause inhibition of urea production (can be caused by genetic or pathogen-induced)
-seen in chronic alcoholism and infection by viral hepatitis (glutamine tends to accumulate when ammonia levels in the blood are abnormally high)
Term
How is nitrogen eliminated in the brain?
Definition
ammonia reacts with alpha-ketoglutarate to form glutamate, which is further converted with NH3 to form glutamine
-gltuamine is sent to the liver/kidnwy
Term
Hepatic encephalopathy
Definition
-accumulation of glutamine in the brain/brain and liver can not get rid of glutamine
-symptoms:
*liver failure:hyperammonemia
*coma/death
*reduced fine motor skills and slurred speech
*confusion, disorientation, delirium
*edema, increase intracranial pressure, and brain stem herniation
-glutamate is inactivated by reuptake/conversion to glutamine
-E metabolism deficits

treatment: neutralization and reduction of the nitrogen-containing toxins
Term
Fate of Amino Acid C skeletons
Definition
strictly ketogenic: Leucine & Lysine (can not be converted to carb form
both ketogenic & glucogenic (can be converted to CAC and can be used to produce phosphoenolpyruvate used for gluconeogenesis): isoleucine, phenylalanine, tryptophan, threonine, tyrosine
Term
Muscle Proteolysis
Definition
-carbon skeletons broken down in muscle for energy produxn
-only occurs after prolonged starvation
-C converted to OAA and supply production of alanine via the transamination of pyruvate
-alanine travels to the liver where the amino group enters urea cycle via glutamate and the C skeleton is used to make pyruvate (level of pyruvate allows the maintenance of blood glucose levels during fasting levels
-in kindey, removal of amino group yields ammonia and glutamate
-urea produced in urea cycle is also transported to the kidney for excretion
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