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What is the fate of intracellular proteins?
Converted into carbon skeletons for TCA cycle and NH4 for synthesis of new amino acids and urea cycle
What is a transamination reaction and what cofactor is used?
Transamination reaction involves the transfer of an amino group from an amino acid to an α-keto acid, catalyzed by an enzyme called aminotransferase.
Cofactor used is PLP (pyridoxal 5'-phosphate) AKA modified Vitamin B6
For many amino acids a-keto glutarate is the amino group acceptor.
What is a-keto-glutarate?
Amino group acceptor in the transamination reaction
Explain a general transamination reaction of alanine for example and a-ketoglutarate
PLP used as cofactor with the enzyme alanine amino transferase to make pyruvate and L-glutamate
How is excess nitrogen in tissues sent safely to liver?
Glutamate accepts amino groups and travels to liver where glutaminase deaminates it and sends NH4 into urea cycle
What is a Schiff base and when is it formed?
This is a N+=C bond and is formed when PLP reacts with amino group
What is glutamate dehydrogenase and where does it occur?
Occurs in mitochondrial matrix of liver cells. Causes glutamate to be converted to a-ketoglutarate
What is special about the cofactor(s) that can be used for glutamate dehydrogenase?
Can use NADP+ or NAD+
Where is urea produced?
Liver
How is ammonia converted to urea and where does this happen?
5 enzymatic steps (4 comprise the urea cycle) and it occurs in cytosol as well as mitochondrial matrix
Where do the nitrogen's in urea come from?
One from NH3 + one from Asp
What enzyme forms carbamoyl phosphate and where does this occur?
In mitochondrial matrix and occurs with the enzyme carbamoyl phosphate synthetase. Happens in 3 reactions but is 1 step.
What is the first reaction of forming carbamoyl phosphate synthetase?
ATP + Bicarbonate causes carbonic-phosphoric acid anhydride to form and ADP is released
What is the second reaction of forming carbamoyl phosphate synthetase?
Carbonic-phosphoric acid anhydride reacts with Pi to form Carbamate
What is the third and final reaction of forming carbamoyl phosphate synthetase?
Carbamate reacts with ATP to form carbamoyl phosphate
What is step 1 of urea cycle and what enzyme is used
Ornithine + Carbamoyl phosphate reacts to make citrulline. The enzyme Ornithine transcarbamoylase is used
What is step 2 of urea cycle and what enzyme is used?
ATP + Citrulline make Citrullyl-AMP which reacts with Aspartate to make arginosuccinate
The enzyme argininosuccinate synthetase is used
What is step 3 of urea cycle and what enzyme is used?
Argininosuccinate becomes arginine and fumarate
The enzyme argininosuccinase is used
What is step 4 of urea cycle and what enzyme is used?
Arginine creates ornithine and urea. H2O is used here
The enzyme Arginase is used
How is urea cycle regulated in the short term?
Short term regulated by N-acetyl glutamate which activates carbamoyl phosphate synthetase I
What is the building blocks for porphyrins(heme) in mammals?
δ-aminolevulinate
What forms δ-aminolevulinate?
Glycine + succinyl-CoA
How does porphyrin synthesis differ in mammals vs plants?
Mammals make it w glycine + succinyl -CoA while bacteria use glutamate
What is porphyria's and how is it caused?
hereditary deficiency in heme synthesis causing porphyrins or intermediates to accumulate.
Can be deficient in any of the 7 enzymes that make a heme which will all cause a different type of porphyrias.
What are purine bases built from in de novo synthesis?
Precursors on a ribose phosphate "Scaffold" Known as PRPP
What are pyrimidine bases built from in de novo synthesis?
Aspartate —> Orotic acid synthesized first then attached to a ribose phosphate.
Where is PRPP from?
The pentose phosphate pathway (PPP)
What is the rate limiting and first committed step of purine synthesis? What enzyme is used in this step?
The synthesis of 5-phospho-β-D -ribosylamine from PRPP + Glutamine
Glutamine-PRPP amidotransferase is the enzyme used
What inhibits glutamine-PRPP amidotransferase?
Essentially any of its products, AMP, GMP, and IMP
How many times is formyl H4 folate used in the purine synthesis pathway and what enzymes use it?
2 times, GAR transformylase and AICAR transformylase
What is the point of using AIR carboxylase in purine synthesis and why is it special?
AIR carboxylase added a carboxyl group (CO2) to AIR and makes it CAIR.
DOES NOT USE BIOTIN like normal carboxylation reacitons
Where will purine synthesis diverge to make AMP/GMP
When IMP (inosinate) is formed the purines will go down there own pathways and be AMP or GMP in two steps
How is AMP formed from Inosinate (IMP)
Step 1: Aspartate is added and GTP is used to make adenylosuccinate. Enzyme used adenylosuccinate synthetase
Step 2: Fumarate is released and adenylosuccinate lyase is used to form AMP
How is GMP formed from Inosinate (IMP)
Step 1: H2O and NAD+ are added to make XMP (Xanthylate). IMP dehydrogenase enzyme is used.
Step 2: Glutamine and ATP are added and the enzyme XMP-Glutamine amidotransferase is used to yield GMP
How is pyrimidine synthesis similar to urea cycle?
Aspartate reacts with Carbamoyl phosphate (used in urea cycle) to make N-carbamoylasparatate
Enzyme used: aspartate trans-carbamoylase
Which pyrimidine is made first and with what intermediate?
UMP (Uridylate) is made first with Orotidylate (OMP).
Enzyme used: orotidylate decarboxylase
How will UMP become CTP
2 Steps
First UMP becomes UTP with 2 ATPs and kinases.
Then Glutamine is added and ATP is added to make CTP with the enzyme cytdylate synthetase.
This makes CTP (Cytidine 5'-triphosphate)
What amino acids are used in purine and pyrimidine synthesis?
Purine synthesis:
Glycine, Glutamine, and Aspartate all are used in intermediates prior to IMP formation then:
Aspartate for AMP, Glutamine for GMP
Pyrimidine synthesis:
Aspartate is building block for both UMP and CTP but Glutamine is also added to CTP
How are Nucleotides broken down to Deoxynucleotides?
Ribonucleotide reductase is used and a NADPH is added to reduce it
Why is the formation of deoxynucleotides a unusual reaction?
Occurs at a non activated carbon atom and a free radical is used
How is the ribonucleotide reductase enzyme regenerated in body?
Reduced glutaredoxin or thioredoxin (small cytoplasmic proteins) help to reform it with the use of multiple reactions involving NADPH and FAD
How is dUMP (Deoxy UMP) converted to dTMP?
dUMP is methylated by thymidylate synthase to generate dTMP.
MTHFR is used here (methylenetetrahydrofolate)
Why would blocking folate synthesis be effective in treating bacterial infections and what drug does this?
Sulfa antibiotics block folate synthesis preventing formation of MTHFR.
MTHFR used as cofactor in many reactions involving amino acids, purines and TMP and blocking this will kill bacteria
How does methotrexate work?
Blocks formation of MTHFR (methylenetetrahydrofolate) which will slow formation of many reactions including CANCERS
How is uric acid made in humans and what is its fate?
Made with purine degradation. Is excreted in urine
How does SCID (Severe combined immunodeficiency) happen and what are the symptoms?
Deficiency in adenosine deaminase which will cause buildup of dATP (inhibits ribonucleotide reductase)
Symptoms: loss of B + T lymphocytes causing no immune system
What will happen to pyrimidines when they are degraded?
The N atoms will be either transferred to glutamate or released as ammonia (excreted as urea)
Carbon skeletons will turn into succinyl-CoA
What is the salvage pathway?
Free purine pases will be salvaged by recombining with PRPP to make nucleotides
Ex: Adenine + PRPP --> AMP + PPi (adenine phosphoribosyltransferase)
What disease interferes with the salvage pathway and what is the cause?
Lesch-Nyhan syndrome(X linked) causing lack of enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT)
This is a interference of the GMP and IMP pathways (Hypoxanthine + PRPP->IMP + PPi)
(Guanine + PRPP -> GMP + PPi)
Causes self mutilation and CNS damage, also gout
