biochemistry 2

• Amino acids and protein metabolism are essential biochemical processes.

Overview of Amino Acids

• Amino acids are classified into nonpolar, aromatic, polar uncharged, positively charged, and negatively charged R groups.
• Glycine, Alanine, and Valine are nonpolar amino acids.
• Phenylalanine, Tyrosine, and Tryptophan are aromatic amino acids.
• Leucine, Isoleucine, and Proline are also amino acids.
• Serine, Threonine, and Cysteine are polar, uncharged R group amino acids.
• Lysine, Arginine, and Histidine are positively charged R group amino acids.
• Aspartate and Glutamate are negatively charged R group amino acids.
• Methionine, Asparagine, and Glutamine are further examples of amino acids.

Proteins

• Proteins are structural tissues for muscles and tendons.
• Proteins transport oxygen as hemoglobin.
• Proteins catalyze biochemical reactions as enzymes.
• Proteins regulate reactions as hormones.
• Approximately 20% of the human body is composed of protein.
• Amino acids are not stored in the body, unlike fats and carbohydrates.
• Excess amino acids are rapidly degraded or catabolized.
• Amino acids must be obtained from the diet, synthesized de novo, or produced from normal protein degradation.
• Nitrogen enters the body mainly through dietary amino acids.
• Nitrogen exits the body as urea and ammonia.
• Nonprotein nitrogen (NPN) compounds come from amino acid metabolism.
• Clinically significant nonprotein nitrogen compounds include urea (45%), amino acids (20%), and uric acid (20%).
• Creatinine (5%), Creatine (1-2%), and Ammonia (0.2%) are also clinically significant nonprotein nitrogen compounds.

Protein Turnover

• Constant protein turnover takes place since proteins and amino acids are not stored in the body, which is approximately 400 g/day.
• Some proteins are constantly synthesized, while others are degraded.
• Nitrogen balance helps maintain a constant amount of body protein in healthy, fed adults: synthesis replaces degradation.
• Protein turnover is the continuous degradation and synthesis of cellular proteins.
• Each day, 300-400 g of body protein, primarily muscle protein, is turned over (degraded and resynthesized).
• The rate of protein turnover varies for individual proteins.
• Short-lived proteins (regulatory and misfolded) are rapidly degraded within minutes to hours.
• Long-lived proteins constitute the majority of proteins in the cell, existing days to weeks.
• Structural proteins like collagen are metabolically stable and measured months to years.

Protein Degradation

• Two major enzyme systems degrade damaged or unneeded proteins.
• The ATP-dependent ubiquitin-proteasome system (cytosol) degrades intracellular proteins
• ATP-independent degradative enzyme system of the lysosomes degrades extracellular proteins.
• Lysosomal acid hydrolases degrade extracellular proteins like plasma and cell-surface membrane proteins used in receptor-mediated endocytosis.
• Degradation of plasma proteins follows loss of a sialic acid moiety.
• Asialoglycoproteins are internalized by liver-cell asialoglycoprotein receptors and degraded.
• Roughly 75% of amino acids are reutilized from protein degradation.
• Excess free amino acids are not stored.
• Amino acids not immediately incorporated into new protein are rapidly degraded.
• The carbon skeletons are converted to amphibolic intermediates.
• Amino nitrogen is converted to urea and excreted in urine.

Amino Acid Levels

• Muscle and liver help maintain circulating amino acid levels.
• There's a balance between release from endogenous protein stores and tissue utilization.
• Muscle generates over half the total body pool of free amino acids.
• The liver houses the urea cycle enzymes for disposal of excess nitrogen.
• After a protein-rich meal (absorptive state), muscles mainly extract branched-chain amino acids (BCAA) i.e. valine, leucine, and isoleucine (essential amino acids).
• In the fasting state, BCAAs, specifically valine, are converted to succinyl-CoA, which enters the citrate cycle and releases muscle energy for the brain.

Glucose-Alanine Cycle

• During extended fasting, skeletal muscle is degraded, thus being an alternative energy source.
• The nitrogen is transaminated to pyruvate, forming alanine via ALT (alanine aminotransferase).
• Alanine is the major amino acid present when muscle (protein) is degraded.
• Alanine is transported from the muscle to the liver, where it is converted to glucose in the glucose-alanine cycle.
• Alanine is synthesized in muscle via transamination of glucose-derived pyruvate.
• Alanine is then released into the bloodstream and taken up by the liver.
• The carbon skeleton of alanine is reconverted to glucose in the liver, released into the bloodstream for muscle uptake and resynthesis of alanine.
• The glucose-alanine cycle recycles carbon skeletons between muscle and liver and transports ammonium to the liver for conversion into urea.
• The Glucose-alanine cycle requires ALT, and is used when in a state of catabolism (muscle breakdown).

Catabolism of Amino Acids

• If not needed for protein synthesis, amino groups, primarily in the liver, are removed.
• BCAAs (leucine, isoleucine, valine) undergoes catabolism primarily in skeletal muscle.
• Amino groups are transferred to alanine and taken to the liver for disposal via the glucose-alanine cycle.
• Transamination involves funneling amino groups to glutamate by transaminases.
• α-Ketoglutarate accepts amino groups from most amino acids, becoming glutamate.
• Oxidative deamination liberates the amino group as ammonia via glutamate dehydrogenase.
• The body then transports ammonia to the liver for synthesis of urea.
• Ammonia is transported to the liver by two mechanisms:
  • Glutamine- most tissues
  • Alanine- muscle (glucose-alanine cycle).
• The first mechanism, found in most tissues, uses glutamine synthetase to combine ammonia (NH3) with glutamate, forming glutamine.
• Glutamine is a nontoxic transport form of ammonia.
• Glutamine then transports to into the liver where it is cleaved by glutaminase to produce glutamate and free ammonia.
• The second transport mechanism is primarily used by muscle.
• Muscle then becomes transamination of pyruvate to form ALANINE.
• Alanine undergoes transportation to the liver, then it is converted to pyruvate.
• Pyruvate synthesizes glucose (gluconeogenesis), which enters the blood and is used by muscle.
• Ammonia is found virtually in all body fluids and exists mainly as ammonium ion (NH4+) at physiologic pH.
• Sources of ammonia include bacterial hydrolysis of urea by urease in the intestine, the purine-nucleotide cycle, and amino acid transamination.
• Reference serum levels less than 35 μmol/L, and excess ammonia is excreted as urea.
• Humans are ureotelic and excrete excess nitrogen as urea which is nontoxic and water-soluble.
  • Excess ammonia is toxic
  • It ionizes to ammonium ion (NH4+)
  • NH4+ converts to urea in the liver in the urea cycle.
  • Urea contains 2 x NH4+

Arginine

• One is from NH4+, and one is from aspartate
• Urea is excreted in urine.
• Arginase activity occurs exclusively in the liver.
• Urea diffuses from the liver and transports in the blood to the kidneys, which is then excreted in urine.
• A part portion of the urea diffuses from blood into the intestine.
• The urea is then cleaved to CO2 and NH3 by bacterial urease.
• The resultig ammonia is partly lost in the feces, and partly reabsorbed into the blood.
• In patients with kidney failure, plasma urea levels are elevated.
• Elevated levels enhance the transfer of urea from the blood into the gut.
• Urease's effects results in a clinically important source of ammonia, contributing to hyperammonemia.
• Ammonia produced by enteric bacteria is absorbed into portal venous blood
• Ammonia produced by tissues is rapidly removed from circulation by the liver, then converts to urea.
• Trace amounts of ammonia are present in peripheral blood because ammonia is toxic.
• It becomes toxic to the central nervous system.
• Ammonia may be toxic to the brain because it reacts with α-ketoglutarate.
• The reaction impairs function to the tricarboxylic acid (TCA) cycle in neurons.
• This further causes energy deficit in the brain and CNS as it depletes α-ketoglutarate.
• High levels of glutamate are linked to hyper-excitability and seizures.
• This causes abnormal excessive neuronal activity in the brain.

Amino Acid Catabolism

• Amino groups are removed initially during amino acid catabolism to form NH3.
  • Catabolism further results in Carbon skeletons
  • Oxidised in citrate cycle
  • Used for gluconeogenesis
  • Converted to fatty acids.
  • 18 amino acids are glucogenic or ketogenic
  • Leucine and lysine are purely ketogenic
  • Amino acid catabolism converges to form seven intermediate products: oxaloacetate, pyruvate, α-ketoglutarate, fumarate, succinyl CoA, acetyl CoA, and acetoacetyl-CoA. These products enter intermediary metabolism, either in the synthesis of glucose or lipid, or in the production of energy through their oxidation to CO2 via the citric acid cycle.
  • Glucogenic Amino Acids yields pyruvate or citric acid cycle intermediates.
  • Intermediates are substrates for gluconeogenesis in the liver and kidney.
  • Ketogenic Amino Acids yields either acetoacetate or acetyl CoA / acetoacetyl CoA.
  • Isoleucine, leucine, and valine are essential amino acids. - These specific amino acids gets metabolized by the peripheral tissues not by the liver - Catabolism begins when a common pathway starts their catabolism - Branched Chain α-Keto Acid Dehydrogenase (BCKDH) is a multi-subunit complex homologous to the Pyruvate Dehydrogenase complex.
  • Genetic deficiency of BCKDH is called Maple Syrup Urine Disease (MSUD).
  • Clinically important amino acids exist. Methionine is a source of methyl groups and precursor of cysteine.
  • Arginine partakes in the urea cycle and is a precursor of nitric oxide.
  • Glutamine stores and transports ammonia, plus it is a precursor to purines and pyrimidines.
  • Phenylalanine is a tyrosine precursor that is elevated in phenylketonuria.
  • Histidine serves as a histamine precursor, and is found to be elevated in histidinemia.
  • Tryptophan is a precursor of serotonin.
  • Alanine transports muscle ammonia and a key glucogenic amino acid.
  • Methionine is a sulphur-containing and essential amino acid.
  • Methionine converts to S-adenosylmethionine (SAM), which serves as the methyl-group donor in one-carbon metabolism.
  • Methionine forms succinyl CoA (heme biosynthesis) and is a cysteine precursor.
  • Source of homocysteine is known as an amino acid whose elevations in the body are associated with atherosclerotic vascular disease and abnormal blood clotting/thromboembolism.

Amino Acids Serves as Precursors for Nitrogen Componds

• Nitrogen containing compounds serves with important physiologic functions: • Porphyrins • Neurotransmitters • Hormones which are catecholamines and thyroid • Purines and Pyrimidines • Creatine • Histamine • Serotonin • Melanin Histamine is a biogenic amine (monoamine) formed from histidine requiring decarboxylase and PLP. Additionally, histamine functions as a chemical messenger for both allergic and inflammatory processes.
  • Histamines plays a role for gastric acid
  • Histamines plays neurotransmission in the brain
  • It is also a vasodilator secretes by mast cells
  • Histamine is from allergies and trauma
  • It does not contain clinic applications for agents, but agents do interference with histamine. These agents include antihistaminics.
• Antiihistamines contain therapeutic functions
  • Serotonin is known as Biogenic amine and monoamine which get call 5 hydroxytryptamine
  • Serotonin is stored at the largest site in the human body specifically for intesial

Serotonin functions:

• A neurotransmitter
• Gets synthesized in CNS
• In the platelets
• Synthesized from trytophan • Pain perceotion Regulation on sleep Appetite Temperature Bload Pressire •Mood causes feeling of well being and cognitive functions

Serotonine Converts into Melatonin

Melatonin is hormone Melatonin secures pines gland. Melatonin secure circadian Circardin is interna clock of biological clock Also determines cycle of sleep Gets bright in the environment in the evenings. •Melatomin belos to timing and releases femate hormones

Creatine

Functions: Synthesized from glycine and arginine, Reversibly phosphorylated to creatine phosphate by the creatine kinase with ATP. Functions an energy reserve Creatine and creatine phosphate spontaneously cyclize at a slow but constant rate to creatinice (NPN compound excreted in urine) Creatinine functions muscle mass •Melanon is on skib havr and eves. Skin havr and eves Tyrosine functions in epiderrmis Melanocyles function to protect sunlight

•Albinism results in sunlight defects