Protein Metabolism 1

Essential amino acids

Required in diet because the body cannot synthesize them due to long complex synthetic pathways. deficiency occurs rapidly during low intake states.

Non-essential amino acids

Can be synthesized endogenously from metabolic intermediates such as glycolysis or TCA cycle substrates simple pathways allow rapid production

Conditionally essential amino acids

Normally non essential, but become essential during hypercatabolic states or limited precursor supply such as trauma burns sepsis pregnancy and growth demand exceeds synthetic capacity

List of essential amino acids

Phenylalanine, Valine, Threonine, Tryptophan, Isoleucine, Methionine, Histidine, Arginine Leucine, Lysine These are also required for protein synthesis and cannot be synthesized de novo

Absolutely non essential amino acids

Alanine, Aspartate, Glutamate these come directly from transamination of pyruvate and TCA intermediates

Conditionally essential amino acid list

Asparagine Cysteine Glutamine Glycine Proline Serine Tyrosine and Arginine in adults dependent on precursor availability and metabolic stress state

Most versatile amino acids

Glutamate Aspartate and Alanine all participate in transamination to shuttle nitrogen and connect with TCA intermediates

Transamination definition

Transfer of amino group between an amino acid and an alpha keto acid mediated by AST and ALT critical step in amino acid interconversion and nitrogen redistribution

AST product

Aspartate formed from oxaloacetate provides second nitrogen for urea cycle via aspartate

ALT product

Alanine formed from pyruvate transports nitrogen from muscle to liver during fasting

Clinical significance of AST and ALT

Markers of liver injury because hepatocyte damage causes leakage of these enzymes into circulation elevated in hepatitis ischemia toxins and acute injury

Glutamine synthesis

Glutamate plus free ammonia via glutamine synthetase

converts toxic ammonia into a transportable form for nitrogen disposal

Glutaminase function

Converts glutamine back to glutamate releasing ammonia

allows kidney to secrete ammonium for acid base balance and liver to generate urea

Asparagine synthesis

Forms from aspartate using amino group from glutamine

requires glutamine for amide nitrogen making it conditionally essential

States increasing glutamine and asparagine demand

Burns trauma sepsis malnutrition and hypercatabolic states

high protein turnover raises nitrogen transport needs

Major roles of glutamine

Primary nitrogen carrier contributes to liver ammonia detoxification, supports renal gluconeogenesis, and acid base regulation glutamine buffers ammonia load and fuels metabolic pathways

Serine synthesis

Derived from glycolysis intermediates links carbohydrate metabolism to amino acid production requiring vitamin B6

Sources of glycine

From glyoxylate via transamination from serine via SHMT with folate from threonine catabolism or from choline degradation

multiple synthesis routes reflect essential role in collagen and nucleotide production

Clinical relevance of glycine

Required for collagen formation purine synthesis folate cycle and rapid cell division during wound healing and growth deficiency affects tissue repair and proliferative tissues

Proline and arginine origin

Derived from glutamate

glutamate serves as precursor for collagen related amino acids and nitrogen metabolism

Physiologic roles of arginine

Required for urea cycle creatine collagen nitric oxide synthesis and T cell activation

demand increases in growth trauma sepsis and immune activation

Cysteine synthesis

Backbone from serine with sulfur from methionine via homocysteine to cystathionine requiring vitamin B6

becomes essential when methionine is low because sulfur must come from diet

Selenocysteine synthesis

Requires serine selenium ATP and specific tRNA inserted cotranslationally

critical for antioxidant enzymes and thyroid hormone activation

Consequences of selenium deficiency

Leads to hypothyroidism accelerated atherosclerosis early heart attack peripheral arterial disease aneurysm tumorigenesis and Keshan cardiomyopathy

loss of antioxidant and deiodinase activity

Tyrosine synthesis

Formed from phenylalanine

becomes non essential only when phenylalanine intake is adequate because reverse conversion cannot occur

Dietary protein strategy during illness

Increase protein intake to compensate for hypercatabolism and avoid worsening nitrogen imbalance

prevents further lean mass loss

Inter organ exchange fed state

Muscle receives amino acids liver converts excess nitrogen to urea tissues undergo repair protein synthesis increases

anabolic hormones promote protein deposition

Inter organ exchange fasting state

Muscle releases alanine and glutamine kidney uses glutamine carbon for gluconeogenesis and excretes ammonium

preserves blood glucose and maintains acid base balance

Role of kidney in fasting

Uses glutamine for gluconeogenesis and excretes ammonium to buffer acid

prevents metabolic acidosis and supports glucose homeostasis

Role of muscle in fasting

Releases alanine and glutamine as nitrogen carriers for liver and kidney

provides substrates for gluconeogenesis and ammonia clearance

Role of brain during hypercatabolic state

Prefers branched chain amino acids because other amino acids are diverted to nitrogen handling

BCAAs bypass hepatic metabolism and enter CNS directlyMain nitrogen excretion form in humans

Urea

humans are ureotelic because urea is water soluble non toxic and easily excreted

Significance of elevated BUN

Indicator of impaired renal excretion not itself a cause of disease

kidneys remove urea so retention reflects renal dysfunction

Forms of nitrogen excretion in body

Ammonia in stool and urine or recycled by liver

multiple pathways prevent toxic accumulation

Ammonia and acid base balance

Renal ammonium excretion helps remove acid equivalents

ammonium formation buffers metabolic acidosis

Rate limiting enzyme of urea cycle

Carbamoyl phosphate synthetase I

controls entry of nitrogen into the urea cycle

Substrates required for CPS I

Ammonium bicarbonate and two ATP

produces carbamoyl phosphate inside mitochondria

Allosteric activator of CPS I

N acetylglutamate

NAG signals increased amino acid breakdown and speeds up urea formation

Regulators of N acetylglutamate synthesis

Arginine and glutamate promote NAG production

links urea cycle activity to amino acid catabolism and arginine abundance

Effect of starvation on urea cycle

Increases urea cycle activity

amino acids are catabolized for gluconeogenesis producing more ammonia that must be detoxified

OTC function

Combines carbamoyl phosphate and ornithine to produce citrulline in mitochondria

first true committed step of urea cycle

Argininosuccinate synthetase function

Combines citrulline with aspartate to form argininosuccinate using ATP

aspartate donates the second nitrogen of urea

Argininosuccinase function

Cleaves argininosuccinate into arginine and fumarate

fumarate returns to TCA and arginine proceeds to final step

Arginase function

Hydrolyzes arginine to urea and ornithine

final step regulating nitrogen excretion

Arginase inhibition

Lysine inhibits arginase

slows urea production when nitrogen turnover is low

Arginase stimulation

Arginine promotes arginase

accelerates urea production when nitrogen load is high

Effect of OTC deficiency

Orotic aciduria with hyperammonemia

carbamoyl phosphate accumulates and spills into pyrimidine synthesis increasing orotic acid while ammonia remains elevated

Effect of pyrimidine synthesis defect

Orotic aciduria without hyperammonemia

defect is downstream so ammonia handling is normal but pyrimidine production is impaired causing megaloblastic anemia

Primary urea cycle disorders

Inborn enzyme deficiencies causing hyperammonemia leading to neonatal seizures altered sensorium and CNS toxicity

ammonia accumulates because nitrogen cannot enter the urea cycle

Most common urea cycle disorder

OTC deficiency

X linked defect causing impaired conversion of carbamoyl phosphate and ornithine to citrulline leading to ammonia buildup

Most severe urea cycle disorder

CPS I deficiency

blocks the first step of urea cycle preventing any ammonia detoxification leading to rapid fatal hyperammonemia

Secondary causes of hyperammonemia

Hepatic dysfunction acute liver failure chronic liver disease GI bleeding high protein load or altered gut flora

liver cannot convert ammonia to urea or receives excess nitrogen

Mechanism of hyperammonemia in GI bleeding

Blood proteins are digested into amino acids and ammonia increases nitrogen load to liver

increased protein substrate overwhelms detoxification

Effect of ammonia fixing bacteria

Increase blood ammonia levels when bacterial overgrowth or dysbiosis is present

gut bacteria metabolize nitrogenous compounds into ammonia

Consequences of increased ammonia entry into CNS

Crosses blood brain barrier leading to neuronal toxicity and astrocyte swelling

ammonia is neurotoxic and disrupts neurotransmission

Role of glutamine synthetase during hyperammonemia

Converts glutamate into glutamine to trap ammonia

protective but leads to glutamine buildup inside astrocytes

Astrocyte swelling mechanism

Excess glutamine increases intracellular osmolarity leading to cerebral edema

osmotic imbalance causes brain swelling seen in hepatic encephalopathy

Effect of ammonia on TCA cycle

Ammonia drives glutamate to glutamine reducing alpha ketoglutarate which lowers ATP production

energy deficit impairs neuronal function

Effect of ammonia on neurotransmitters

Depletes glutamate and GABA pools

low glutamate reduces excitatory tone causing coma and low GABA reduces inhibition causing seizures

Clinical manifestation of hyperammonemia

Fluctuating consciousness seizures cerebral edema personality changes and coma

imbalance of neurotransmission and cell swelling

Hepatic encephalopathy mechanisms

Direct ammonia neurotoxicity astrocyte swelling energy deficit and imbalance between excitatory and inhibitory neurotransmitters

combined metabolic and osmotic injury leads to CNS dysfunction

Goal of hepatic encephalopathy treatment

Lower ammonia reduce nitrogen turnover and address triggers

preventing further ammonia accumulation reverses symptoms

Triggers of hepatic encephalopathy

Infection trauma GI bleeding dehydration constipation high protein intake or worsening chronic liver disease

all increase ammonia production or reduce clearance

Protein strategy in hepatic encephalopathy

Low protein diet with use of ketoacids

ketoacids accept nitrogen during transamination reducing ammonia burden

Role of lactulose in hepatic encephalopathy

Osmotic laxative that acidifies gut trapping ammonia as ammonium and promotes excretion

decreases ammonia absorption and clears ammonia producing bacteria

Role of rifaximin in hepatic encephalopathy

Nonabsorbable antibiotic that eliminates ammonia producing gut bacteria

reduces intestinal ammonia generation

Role of neomycin in hepatic encephalopathy

Antibiotic used to suppress colonic bacteria that produce ammonia

decreases ammonia production but has ototoxicity and nephrotoxicity risks

behind reducing stress in hepatic encephalopathy

Stress increases catabolism and nitrogen turnover which elevates ammonia

lowering metabolic demand reduces ammonia production

Why high protein worsens hepatic encephalopathy

Increases nitrogen load that liver cannot detoxify

more amino acids produce more ammonia during metabolism

Fate of ammonia from gut

Bacterial metabolism in colon produces ammonia which enters portal circulation and returns to liver for detoxification or is excreted in stool

gut flora contribute significantly to ammonia load

Ammonia excretion routes

Eliminated through urine as ammonium or in stool or recycled through liver urea cycle

multiple pathways prevent toxic systemic buildup

Renal role in ammonia handling

Converts glutamine to ammonium for excretion supporting acid base balance

ammonium excretion removes acid equivalents during metabolic acidosis

Ammonium and acid base balance

Ammonium secretion in kidney buffers acid and prevents acidosis

ammonium formation consumes protons helping maintain pH

Indicator of increased nitrogen turnover

Elevated glutamine and increased urea cycle activity

body accelerates ammonia detoxification when protein catabolism rises

Effect of excess glutamine synthesis in hyperammonemia

Depletes glutamate and alpha ketoglutarate reducing ATP generation

diversion of TCA intermediates impairs energy metabolism in neurons

Reason cerebral edema develops in hyperammonemia

Astrocytes accumulate glutamine causing osmotic swelling

intracellular osmotic shift produces brain edema

Why decreased glutamate causes coma

Low glutamate decreases excitatory neurotransmission

inadequate stimulation of cortical neurons lowers consciousness

Why decreased GABA causes seizures

Low GABA decreases inhibitory tone

loss of inhibitory neurotransmission destabilizes neuronal firing

Why hyperammonemia causes both coma and seizures

Reduced glutamate causes coma while reduced GABA triggers seizures

ammonia disrupts both excitatory and inhibitory neurotransmitter pools

Effect of chronic liver disease on ammonia

Reduces conversion of ammonia to urea leading to elevated circulating ammonia

impaired hepatocyte function limits detoxification

Reason ammonia toxicity worsens with muscle wasting

Muscle normally consumes ammonia by forming glutamine so loss of muscle increases circulating ammonia

decreased peripheral ammonia buffering leads to CNS accumulation

Why GI bleeding increases ammonia load

Blood proteins are degraded into amino acids that produce ammonia during catabolism

increases nitrogen substrate entering liver

Purpose of using ketoacids in hepatic encephalopathy

Ketoacids accept nitrogen during transamination producing amino acids without generating ammonia

bypasses ammonia producing steps

Effect of constipation on ammonia levels

Slows transit allowing more bacterial ammonia production and absorption

prolonged stool contact increases nitrogen breakdown

Mechanism of lactulose acidification

Lactulose fermentation produces short chain fatty acids that acidify colon converting ammonia to ammonium which is non absorbable

traps nitrogen in gut for excretion

Reason rifaximin is preferred antibiotic

Nonabsorbable minimal systemic toxicity effective at suppressing ammonia producing gut bacteria

reduces ammonia without harming host

Reason neomycin is second line

Effective but causes nephrotoxicity and ototoxicity

systemic toxicity limits chronic use

Overall treatment goal in hepatic encephalopathy

Reduce ammonia production enhance excretion and correct precipitating factors

restores neurotransmitter balance and decreases cerebral edema

Reason starvation increases urea cycle activity

Starvation increases amino acid catabolism for gluconeogenesis producing more ammonia requiring faster detoxification

increased protein breakdown feeds more nitrogen into urea pathway

Effect of increased arginine on urea cycle

Arginine stimulates N acetylglutamate production which activates CPS I and accelerates urea cycle

arginine signals high nitrogen load

Effect of lysine on arginase

Lysine inhibits arginase slowing conversion of arginine to urea

provides negative feedback when nitrogen turnover is low

Connection between fumarate from urea cycle and TCA cycle

Fumarate reenters TCA cycle supporting energy metabolism

links nitrogen disposal to carbon energy pathways

Main nitrogen sources entering urea cycle

Ammonium via CPS I and aspartate via argininosuccinate synthetase

these two contribute the two nitrogens of urea

Reason citrulline is exported from mitochondria

Subsequent urea cycle steps occur in cytosol

spatial separation organizes the cycle between mitochondrial and cytosolic compartments

Effect of excessive nitric oxide synthase activity

Consumes arginine reducing availability for urea cycle and increasing risk of nitrogen imbalance

arginine diverted to NO lowers substrate for urea formation

Clinical scenario with high NO production

Septic shock

inflammatory cytokines induce iNOS leading to excessive NO and arginine depletion

Clinical effect of low tyrosine in critical illness

Depletion of catecholamines and thyroid hormones

tyrosine is precursor for epinephrine norepinephrine dopamine and thyroid hormones

Clinical effect of low proline and glycine in trauma

Impaired collagen synthesis and wound healing

both are major components of collagen matrix

Reason asparagine becomes semi essential when glutamine is low

Asparagine synthesis requires amino group from glutamine

glutamine depletion limits asparagine availability

Reason cysteine becomes semi essential

Cysteine obtains sulfur from methionine so low methionine lowers cysteine synthesis

dependence on essential amino acid makes cysteine conditional