Biochemistry: Nitrogen Metabolism Lec 5

Nitrogen metabolism

The set of processes by which nitrogen is acquired, processed, and disposed in the body, including amino acid catabolism, transamination/deamination, the urea cycle, and synthesis of nitrogen-containing compounds.

How are free amino acids taken into the cell?

They are taking up through active transport in the intestine cells then released through passive transport by faciliated diffusion. Ultimate end is the liver

Amino acids disposal of nitrogen

A principle that amino acids are not stored; excess nitrogen is rapidly disposed via degradation and excretion, mainly as urea.

Transamination

Transfer of an amino group from an amino acid to an α-keto acid, producing a new amino acid and a new α-keto acid; catalyzed by aminotransferases.

Deamination

Removal of the α-amino group to release ammonia; deamination of glutamate yields α-ketoglutarate and NH3; ammonia enters the urea cycle in the liver

Urea cycle

Liver pathway that converts ammonia to urea for excretion; involves CPS I, ornithine, citrulline, argininosuccinate, and arginase; regulated by N-acetylglutamate.

Carbamoyl phosphate synthetase I (CPS I)

Mitochondrial enzyme; rate-limiting step of the urea cycle; activated by N-acetylglutamate.

N-acetylglutamate

Essential allosteric activator of Carbamoyl phosphate synthetase 1 enabling the urea cycle to proceed.

Ornithine

Amino acid that cycles in mitochondria; regenerated and transported into mitochondrion in the urea cycle.

Citrulline

Citrulline is formed from ornithine and entered into the urea cycle; exported to the cytosol for further reaction.

Argininosuccinate synthetase

Enzyme that condenses citrulline with aspartate to form argininosuccinate.

Argininosuccinate lyase

Enzyme that cleaves argininosuccinate to yield arginine and fumarate.

Arginase

Enzyme that converts arginine to urea and ornithine, completing the urea cycle.

Hyperammonemia

patients with kidney failure plasma urea level is elevlated promoting a greater transfer of urea from blood to gut

Glucogenic amino acids

Amino acids whose catabolism yields pyruvate or TCA cycle intermediates.

Ketogenic amino acids

Amino acids whose catabolism yields acetyl-CoA or acetoacetyl-CoA (or acetoacetate).

Maple Syrup Urine Disease

Blockage of Leucine Valine and Isoleucine (branched side chain) leads to accumulation and urine smells sweet (causes major problems)

Phenylketonuria

Phenylalanine not being broken down which leads to accumulation due to deficiency of phenylalanine hydroxylase. Avoid a aspartatete/asparte acid diet because it gets reduced to PHE and can lead to mental retardation

Albinism

LACK of tyrosinane and thus melanin is not produced. Can get skin cancer easily

Precursors of AA and Protein

Porphins, neurotransmitters, hormones, Purine, and Pyrimidines

Protein turnover

Simultaneous synthesis and degradation of proteins; maintains constant body protein in a fed, healthy adult.

Amino acid pool

All free amino acids in cells and extracellular fluids; maintained by synthesis/degradation of proteins.

Porphyrins Metabolism

Cyclic nitrogen-containing binds to metal ions and the most prevelant in human is heme center Tertapyrolle ring of Protoprophyrin IX (9)

Heme

Prosthetic group of hemoglobin, myoglobin, chhromes, catalase, nitric oxidise synthease, and peroxidase

Major Sites of Heme Biosynthesis

LIver and Erthoryctes-producing cells of the bone marrow (bone marrow accounts for 85%) immature RBC still have mitochondria

ALAS1

First enzyme in heme synthesis that inhinits Heme

ALAS2

Activates Iron in Hemesynthesis

Lead poisoning (lead inhibits heme enzymes)

Lead inhibits ALA dehydrogenase and ferrochelatase, causing accumulation of toxic intermediates and porphyrias in urine

Where are RBCs degraded and how long

Cycle of 120 days in liver and spleen

Heme degradation

Degradation of heme primarily in liver/spleen to biliverdin, then bilirubin, then bilirubin glucuronide for excretion.

Biliverdin → bilirubin

Biliverdin is reduced to bilirubin from Heme through biliverdin reducatse; bilirubin is toxic and is conjugated for solubility and excretion

Jaundice (icterus)

Yellow discoloration due to elevated bilirubin levels in blood and tissues.

Catecholamines

Dopamine, norepinephrine, and epinephrine; biologically active amines involved in neurotransmission and fight-or-flight responses.

Important enzyme of Synthesis of Catecholamines

PLP = Pyridoxal phosphate which is from Vitamin B-6

Dopamine synthesis enzymes

Tyrosine hydroxylase, DOPA decarboxylase ending with dopamine to non-epi- epi

Insufficient Dopamine disease

Parkinsons - neurodegenerative movement due to it depresson leads to misfolder protein and loss of dope-producing cells

MAO and COMT

Enzymes that inactivate catecholamines: monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). (OH-methylation)

Vanillylmandelic acid (VMA)

End product of catecholamine catabolism from Epinephrine + norepinephrine

Homovanillic acid (HVA)

End product of Catecholamine Catabolism from Dopamine

Serotonin

Derived from TRYPTOPHAN, involved in mood, sleep, appetite, bowel function, etc.

Histamine

amine produced from histidine by histidine decarboxylase; mediates allergic responses and gastric secretion.

Creatine phosphate

Derived from Arginine + Glycine → creatine w/ ATP —> Creatine phosphate. High-energy reserve in muscle; donates phosphate to ADP to rapidly regenerate ATP during short, intense activity.

Melanin

Derived from Tyrosine

Nucleotide metabolism

Pathways for synthesis and degradation of nucleotides, including purines and pyrimidines.

Purines vs pyrimidines

Purines: adenine and guanine bases; pyrimidines: cytosine, thymine, uracil; bases pair with sugars to form nucleosides and nucleotides.

Remembering Bases

Sine - Purines
Pryrimidines - Dine
Ends in Tide - ends in Ate

DeoxyNuceloside- ends in Sine for Purines and Dine for Pyrimidine
Ribonucleoside - will have no- for PURINE and tidine for PYR

Purine synthesis Location

Liver

PRPP Synthase

Ribose 5 Phosphate w/ ATP → 5-Phosphoribosyl-1Pyrophosphate PRPP (inhibited by Purine Ribonucleotide)

End Product of Purine Synthesis

Inosine Monophosphate (IMP) from Glycine + Aspartate

• which further converts to AMP or GMP.

Ribonucleotide Reductase

enzmyes respondible for giving the deoxyribose form

Final Product of Degradation of Purine

Degradation of Purine is Uric Acid

Gout

Hyperuricemia with urate crystal deposition; often due to underexcretion; treated with allopurinol to inhibit xanthine oxidase.

Allopurinol

An inhibitor that inhibits the precursor Xanthine from Xanthine oxidase which forms Uric Acid. If Uric Acid isn’t excreted crystal form in joints causing gout

Purine analogues as drugs

Thio-, cytarabine, 5-azacytidine, gemcitabine, and 6-mercaptopurine interfere with nucleotide metabolism or DNA synthesis for cancer/immunosuppression.

6-mercaptopurine (Purinethol)

Purine analogue that inhibits IMP to AMP/GMP conversion; Way of killing cancer cells by killing DNA

Hydroxyurea

Enzymes that inhibits Ribonucletide Reductase (used to treat Leukemia)

What enzyme makes up 60% of our Amino Acids

Glutamine

CTP Synthethase

UTP → CTP through Glutamine using ATP + H2O

Folate Acid derivaties (tetra)

From Vitamin B9 and from Serine

Pyrimidine synthesis

Pathway producing UMP, UDP, UTP, and CTP; involves ; dTMP is produced from dUMP through Thymidylate synthase.

Products of Prymidine Degradation

Beta- amino Acids Co2 and NH3

Nucleotide vs Nucleoside

Nucleotide: Sugar + Phosphate + Base
Nucleoside Sugar + Base

Dihydrofolate reductase (DHFR)

Enzyme that reduces dihydrofolate to tetrahydrofolate; essential for thymidylate synthesis and purine synthesis.(uses NADPH) (Di-Tetra)

Thymidylate synthase

Enzyme that converts dUMP to dTMP; inhibited by 5-FU, reducing DNA synthesis.