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The metabolism of nitrogen-containing molecules (nucleotide synthesis…
The metabolism of nitrogen-containing molecules
amino acids and nucleoside bases
amino acid degradation and the urea cycle
proteins ingested in the diet are digested into amino acids or small peptides that can be absorbed by the intestine and transported in the blood
another source is the degradation of defective or unneeded cellular proteins
amino acids do not be stored like carb. and far; excess amino acids are first used as building blocks for anabolic reactions, such as protein and nucleotide synthesis
a safe of excess amino acids is important because excess N in the form of ammonia is toxic
N removal is the 1st step in the degradation of amino acids
major degradation site in mammal is in liver
the alpha-amino gr. of many amino acids is transferred to alpha-ketoglutarate to form glutamate, which undergoes oxidative deamination to yield ammonium ion. ; by aminotransferases
glutamate dehydrogenase produces alpha-ketoglutarate
the N atom that is transferred to alpha-ketoglutarate in the transamination reaction is converted in to free ammonium ion by the oxidative deamination of glutamate, regenrating alpha-ketoglutarate
the reaction is catalyzed by glutamate dehydrogenase. the reaction is driven forward by the rapid removal of ammonium ion
glutamate dehydrogenase can use either NAD+ or NADP+ to oxidze glutamate
serine and threonine can be deaminated
they can be directly converted to NH4+ these direct deamination are catalyzed by serine dehtdrogenase and threonine dehydrogenase
peripheral tissues transport N to the liver
the liver cannot deaminated the branched-chain amino acids: leu, val and iso, so the muscle use the branched-chain amino acids as a source of fuel
the ammonia is transferred to glutamate, and then to pyruvate to yield alaine
N can also be transported in the form of glutamine by the systhesis of glutamine from glutamate and NH4+ in an ATP-depedent reaction
ammonium ion is converted into urea in most terrestrial vertebrates
most aquatic species are ammonotelic, excreting amino N as ammonia. terrestrial animals required pathways for N excretion that minimize toxicity and water losss
excret urea ureotelic
excret uric acid urictelic
urea cycle
1st: the coupling of free NH4+ and HCO3-
the reaction in the MT matrix and is cat. by anz.
2ATP are required, making the synthesis of carbonyl phosphate irreversible
CPS I is the key enz. for urea syn
2nd: addition of AMP to citrulline and the second N
enz. ariginiosuccinate synthase first activate citrulline by an addition of AMP
then, the amino gr. from aspartate is transferred to citrully-AMP to form argninosuccinate synthase
3rd: ariginiosuccinate is cleaved into Arg and fumarate
4th: enz. arginase cleaves Arg to yield ura and ornithine
the activity of the urea cycle is regulated at 2 levels
the flux of N through the urea cycle in an individual animal varies with diet
C atoms of degraded amino acids emerges as major metabolic intermediates
amino acid synthesis
6 amino acids are degraded to pyruvate
alpha-ketoglutarate is another point of entry into metabolism
succinyl coA is a point of entry for several nonpolar amino acids
oxygenases are required for the degradation of aromatic amino acids
the nitrogen cycle
the nitrogenase complex fixes N
nitrogenase consist of 2 proteins: reductase and nitrogenase
at least 16 ATP are hydrolyzed for each molec. of N2 reduced
the product of reduction, NH3, is a base in aqueous solutions, attracting a proton to form NH4+
ammonium ion is incorporated into an amino acid through glutamate and glutamine
amino acids are made from intermediates of major pathways
some amino acids can be made by simple transmination reaction
serine, cysteine, and glycine are formed from 3-phosphoglycerate
in the formation of glycine, the side-chain methylene gr. of serine is transferred to tetrahydrofolate
S-adenosylmethionine is the major donor of methyl groups
feedback inhibition regulates amino acid biosynthetic
the rate of synthesis of amino acids depends on the amount of the biosynthetic enz, and on their activities
nucleotide synthesis
salvage pathways
preformed bases are recovered and reconnected to the ribose unit
salvage pathway recycle pyrimidine bases
thymine is released from degraded DNA and RNA is salvaged in 2 step
thymidine is then converted into a nucleoside b thymidine kanse
thymine is converted into the nucleside thymidine by thymidine phosphorylase
the purine ring is assembled on ribose phosphate
De novo pathways
the final prod. of the purine stn. is IMP: fumarate leaves, and the 2nd formly gr. is added+ cyclization completes the syn. of IMP
the base itself is synthesized from simpler starting mat, including amino acids
the amino acids glycine, glatamine and aspartate are required precusors
purine bases can be recycled by salvage pathways
2 salvage enz.with different recover purine bases
ribonucleotides are reduces to deoxyribonucleotides
the same enz. (ribonucleotide reductase) acts on all 4 ribonucleotides
thymidylate si formed by the methylation of deoxyuridylate
feedback inhibition
pyrimidine biosynthesis is regulated by aspartate transcarbamoylase (ATCase). ATCase is inhibited by CTP, the final prod. of pyrimidine biosyn.
ATP stimulates ATCase
this type of regulation serves to balance the purine and pyrimidine pools
Gout
high serum levels of urate induce painful joint disease
urate is the final prod. of purine degradation and it excrete in the urine