Urea Cycle 2/3

Urea

terrestrial vertebrates and sharks excrete nitrogen in the form of ____ which is much less toxic then ammonia and has a high solubility

Uric acid

birds and reptile excrete nitrogen as ___ which is mostly insoluble and excreted as paste to allow for those animals to conserve water

Humans and great apes

excrete nitrogen as both urea and uric acid

Amino acids

urea acids excretion in humans is from …

Purines

uric acid excretion in humans is from …

NH2CONH2

formula of urea (need to know structure)

NH4+

ammonia (ammonium ion)

NTK structure

uric acid NTK structure

Toxic

release of free ammonia is _____

Alpha keto acids

amino groups are captured as ___ in transamination

Transamination

allows transfer fo an amine to a common metabolite (alpha ketoglutarate) and generate a trafficable amino acid (eg glutamate)

Alanine and glutamine

amino acids from muscle

Aminotransferases

catalyzes transamination (specific one for each amino acid)

Pyridoxal phosphate cofactor

cofactor needed for transamination

Glutamate

made from the transfer of one amine to alpha ketoglutarate

Glutamine

made from the SECOND transfer of an amine group

Glutamine synthetase

makes glutamine from the transfer of amino groups

L glutamine

acts as a temporary storage of nitrogen and can donate the amino group when needed for amino acid biosynthesis

Reversible

transamination reactions are ___

Alpha ketoglutarate to glutamate

one reaction of transamination using a ketoglutarate

L amino acid to keto acid

one reaction of transamination using an amino acid

L amino acid to L glutamate

the amino group is transferred from ___ to ____ in a general transamination reaction

PLP

intermediate, enzyme bound carrier of amino groups

Aldehyde

PLP form can react reversibly with amino groups

Aminated

PLP form can react reversibly with carbonyl groups

Ping pong displacement

the use of PLP in transamination is part of a ____ reaction mechanism

Internal aldimine

this covalently links the PLP to the enzyme in the resting enzyme

Active site lysine

the internal aldimine to pyridoxal phosphate covalent link is made by a nycelophilic attack fo the amino group of an _______________

Racemization

PLP also catalyzes the ____ of amino acids beyond transamination and decarboxylation

L aa to Schiff base to Quinonoid int to D amino acid

the racemization reaction order catalyzed by PLP

Decarboxylation

PLP also catalyzes the ____ of amino acids beyond transamination and racemization

L aa to Schiff base to quinoid int w CO2 lose to amine

decarboxylation reaction carried out by PLP

Glutamine synthetase

in most tissues this is used to convert glutamate to glutamine

Muscle

the transamination of pyruvate and glutamate into alanine and alpha ketoglutarate is heavily use in the ____ tissue

Glutamine

extra ____ is processed in the liver

Muscle

location where glutamine synthetase converts L glutamate to gamma glutamyl phosphate to L glutamine in the ____

L glutamate to gamma glutamyl phosphate to L glutamine

glutamine synthetase reaction

Glutaminase

in the liver mitochondria this converts glutamine to glutamate with the by product of NH4+ which goes to the urea cycle

Liver Mitochondria

where is the reaction catalyzed by glutaminase that converts L glutamine to L glutamate with the product of NH4+

Uses ATP

does glutamine synthetase use or make energy when converting glutamate to glutamine

Glucose alanine cycle

transports ammonia form muscle to liver

Lactic acid

if pyruvate made from glycolysis is not eliminated this will build up

Alanine

pyruvate can be converted to __ for transport to the liver

Alanine aminotransferase

converts pyruvate to alanine with the help of glutamate and alpha ketoglutarate

Muscle

in the ____ pyruvate is converted to alanine

Liver

in the ___ alanine is converted to glutamate

NH4+ production and the urea cycle

why does blood alanine need to be converted to glutamate when it enters the liver

Liver

the major portion of waste nitrogen from degraded amino acids ends up in the ____

Glutamate dehydrogenase

ammonia collected in glutamate is removed by ________

Oxidative deamination

occurs within the mitochondrial matrix of the liver and can use NAD+ or NADP+ as the electron acceptor where ammonia is processed into urea for excretion

Trans deamination

this is the process that combines transamination and oxidative deamination

Orange colored cats always ask for awesome umbrellas

mnemonic device for urea cycle

Ornithine, carbamoyl phosphate, citrulline, aspartate, arginosuccinate, fumarate, arginine, urea

order of substrates in the urea cycle

Mitochondria

excess glutamate is metabolized where?

Carbamoyl phosphate

ammonia is recaptured by the synthesis of … as it is the first nitrogen acquiring reaction of the urea cycle

Nitrogen acquiring

the carbamoyl phosphate synthesis is a ____ step of the urea cycle

ATP

bicarbonate is phosphorylated by ___ to form carbonic phosphoric acid anhydride

Carbonic phosphoric acid anhydride

when bicarbonate is phosphorylated by ATP what is produced

Ammonia

this displaces phosphoryl group on carbonic phosphoric acid anhydride to make carbamate

Carbamate

what is the product of the ammonia displacement of the phosphate group on carbonic phosphoric acid anhydride?

ATP

what phosphorylates carbamate to make carbamoyl phosphate?

Carbamoyl phosphate

this is made when ATP phosphorylates carbamate

Bicarbonate, carbonic phosphoric acid anhydride, carbamate, carbamoyl phosphate

order of substrates in carbamoyl phosphate synthesis

Carbamoyl phosphate synthetase

what enzyme makes carbamoyl phosphate?

Cytosol

the majority of the urea cycle occurs where

Ornithine

in order to move to the cytosol for the urea cycle, carbamoyl phosphate must condense with ____ to make citrulline (this reaction releases a phosphate)

Phosphate into mitochondrial matrix

when ornithine and carbamoyl phosphate condense to make citrulline, what is released and to where?

Citrulline

when carbamoyl phosphate and ornithine are condensed together what is produced? This product can be transported to the cytosol for the urea cycle

Phosphorylate

to activate the citrulline in the cytosol what do you do to it?

Citrullyl AMP intermediate

citrulline that has been phosphorylated by ATP forms…

Aspartate

this is formed in the mitochondrial matrix, but enters the urea cycle after the citrullyl AMP intermediate is made and will form arginosuccinate with the help of arginosuccinate synthetase

arginosuccinate synthetase

enzyme that converts aspartate to argininosuccinate with the by product of AMP

AMP

what is released in the arginosuccinate synthetase reaction in the urea cycle

Fumarate

this is made from arginosuccinate via argininosuccinase and leaves the urea cycle

Arginine

this is made from argininosuccinase and remains as a part of the urea cycle

Argininosuccinase

enzyme that converts argininosuccinate into fumarate and arginine

Arginase

converts arginine to ornithine with the product of urea

Ornithine trans carbamoylase

catalyzes the condensation of ornithine and carbamoyl phosphate into citrulline

Citrulline to ornithine

part of the urea cycle that happens in the cytosol

Ornithine to citrulline

part of the urea cycle that happens in the mitochondrial matrix

Entry of aspartate

this is the second nitrogen acquiring reaction of the urea cycle

AMP

good leaving group on citrullyl AMP that promotes the attack of aspartate to the imide carbon to produce argininosuccinate

Imide carbon

electrophile on citrullyl AMP that is attacked by asparate to make argininosuccinate

Arginine

can enter the urea cycle after argininosuccinase cleaves fumarate from argininosuccinate, resulting in arginine, but also can additionally add extra ____ at this point

Arginase

cleaves both nitrogens added in the urea cycle from arginine resulting in a free urea

Nitric oxide

vasodilator produced in inner most cells of vasculature, incidentally discovered as a drug for angina in the 1860s

Cytosolic urea cycle enzymes

nitric oxide by product will be processed back into arginine by _____

malate-alpha ketoglutarate, glutamate-aspartate, glutamate-OH-

these are the transporters needed for communication between the citric acid and urea cycle, which is needed between the mitochondrial and the cytosol

aspartate argininosuccinate shunt

links urea and citric acid cycles

malate alpha ketoglutarate shuttle

moves high energy e- carriers (NADH) into mitochondrial matrix

n acetylglutamate

carbamoyl phosphate synthetase I is activated by _______

n acetylglutamate synthase

forms n acetylglutamate

glutamate and acetyl coa

n acetylglytamate is made when ___ and ___ concentrations are HIGH and it is activated by arginine

high protein diet, starvation

expression of urea cycle enzymes increase when needed which would be during which dietary conditions?

Arginine

this amino acid tells us to upregulate the urea cycle

Hyperammonia

too much ammonia is known as …

Ammonia toxicity

results from liver failure that causes an increased concentration of _____ which will diffuse across the blood brain barrie and increased synth of glutamate from a ketoglutarate which means a ketoglu is lost from the CNS so the TCA and ATP production decreases, alters neurotransmission

Benzoate and phenylbutyrate

toxicity of urea cycle deficiencies can be relived by ___ and ____

Benzoyl-Gly and phenylAc-Gln

the use of benzoate and phenylbutyrate leads to the excretion of ___ and ____ which results in the cells being short of Gly and Gln so they consume NH4+ without the urea cycle