Which amino acids are purely ketogenic?

Only Lysine and Leucine are purely ketogenic - they break down exclusively into acetyl-CoA and cannot generate glucose.

What enzyme is deficient in phenylketonuria?

Phenylalanine hydroxylase (PAH) is deficient in classic PKU, blocking conversion of phenylalanine to tyrosine. Tetrahydrobiopterin (BH4) is the required cofactor.

What is the GABA connection in hepatic encephalopathy?

Liver failure raises ammonia. Elevated ammonia drives alpha-ketoglutarate amination to form glutamate. Excess glutamate is converted to GABA by glutamate decarboxylase, producing excessive CNS inhibition and encephalopathy.

Why is bicarbonate given before lifting a crush injury victim?

Myoglobin is an acidic protein with high renal affinity. Bicarbonate alkalinizes the urine, ionizing myoglobin and reducing its tubular reabsorption. Starting the drip before removing the compressive object prevents the flood of myoglobin from reaching uncharged kidneys.

All Amino Acids: Classification, Metabolism, and Clinical Applications

Home Biochem Amino Acids All Amino Acids

AA Backbone

Phenylketonuria neonatal screening blood spot card

PKU Screen

Alkaptonuria

Aromatic Amino Acid Cascade

Animated particles show metabolic flow. Tap the red X to toggle the PKU block annotation.

⭐ The Special One

Gly

Glycine

Simplest Amino Acid

UniqueNO chiral carbon: R group = just H, so no asymmetric center

FunctionInhibitory neurotransmitter in the spinal cord

Board HitTetanus toxin blocks glycine release from spinal cord: muscles can't relax, diaphragm locks up, respiratory failure

💎 Aromatic Amino Acids Big, bulky ring structures

Phe

Phenylalanine

Aromatic • Essential

EnzymeRecognized by chymotrypsin (cuts to its right side)

EnergyBoth glucogenic AND ketogenic

DiseasePKU: can't convert Phe to Tyr via PAH. Musty/mousy odor, intellectual disability, fair skin, blue eyes (Tyr makes melanin)

Trp

Tryptophan

Aromatic • Essential

MakesSerotonin and melatonin

AlsoWithout Trp: can't make niacin (B3) at 60:1 ratio. Pellagra: 3 D's (Dermatitis, Diarrhea, Dementia)

DepletedCarcinoid syndrome uses all Trp for serotonin overproduction, leaving none for niacin synthesis

DiseaseHartnup disease: defective neutral AA transporter. Trp spills in urine, pellagra-like rash, intermittent ataxia

EnergyBoth glucogenic AND ketogenic

Tyr

Tyrosine

Aromatic • Hydroxyl

MakesCatecholamines: Dopamine, Norepinephrine, Epinephrine

AlsoMakes melanin (skin pigment) and thyroid hormones (T3/T4)

BondsExtra OH group: involved in O-linked bonds and phosphorylation targets

➕ Basic Amino Acids Extra NH3+ = positive charge at physiologic pH

Lys

Lysine

Basic • Essential

ChargePositive: extra NH3+ group

EnzymeRecognized by trypsin (cuts to its right side)

EnergyPurely KETOGENIC: one of only 2 (Lys + Leu) 🔑Only ketogenic pair: Lysine + Leucine. "Can't LIE about ketogenic: Lys and Leu."

MigratePositive: migrates toward cathode (-)

Arg

Arginine

Basic • Conditionally Essential

ChargePositive: guanidinium group

EnzymeAlso recognized by trypsin

FunctionPrecursor to nitric oxide (NO) via nitric oxide synthase: vasodilation

ConditionalSynthesizable from citrulline in healthy adults; essential during stress, growth, or illness

His

Histidine

Basic • Essential

ChargeImidazole ring: pKa ~6, buffers at physiologic pH (only amino acid that does this)

MakesHistamine: decarboxylation of histidine. Remember allergy, acid, mast cells

In HbAHis 146 (beta chain) forms the Bohr effect salt bridge: releases O2 in acidic tissues

➖ Acidic Amino Acids Extra COO- = negative charge

Asp

Aspartate

Acidic

ChargeNegative: extra COO- group

FunctionReinforcement of behavior via the NMDA pathway (gambling, addiction)

DrugMemantine blocks NMDA receptor: treats Alzheimer's disease

MigrateNegative: migrates toward anode (+)

Glu

Glutamate

Acidic

ChargeNegative: extra COO-

FunctionMain excitatory neurotransmitter in the brain

GABA LinkGlutamate → GABA via glutamate decarboxylase. This pathway drives hepatic encephalopathy (see below).

💥 Sulfur-Containing Disulfide bonds • protein stability

Cys

Cysteine

Sulfur • Disulfide King

ContainsSulfur: highest sulfur content of any amino acid

FunctionMakes disulfide bonds (S-S): critical for protein tertiary structure

Board HitPIGI hormones: Prolactin, Insulin, Growth Hormone, Inhibin. All have lots of disulfide bonds. 🔑PIGI: Prolactin, Insulin, Growth Hormone, Inhibin. Like a piggy bank held together by cysteine S-S bonds.

Met

Methionine

Sulfur • Essential

ContainsSulfur

SpecialStart codon (AUG) codes for Met: first amino acid in every protein

AlsoDonates methyl groups via SAM (S-adenosylmethionine): methylation reactions throughout the body

🔗 Amide Amino Acids N-linked bonds • end in "-ine"

Asn

Asparagine

Amide

BondsInvolved in N-linked bonds (glycosylation)

RememberEnds in "-ine": has an extra amine group (NH2)

Gln

Glutamine

Amide

BondsInvolved in N-linked bonds

FuelMajor fuel for enterocytes (intestinal cells) and rapidly dividing immune cells

💧 Hydroxyl Amino Acids O-linked bonds • phosphorylation targets

Ser

Serine

Hydroxyl

BondsInvolved in O-linked bonds

SpecialFound in the active site of serine proteases: trypsin, chymotrypsin, elastase, thrombin

ExtraHas extra -OH group: major phosphorylation target for kinases (Ser/Thr kinases)

Thr

Threonine

Hydroxyl • Essential

BondsInvolved in O-linked bonds

EnergyBoth glucogenic AND ketogenic

💪 Branched-Chain Amino Acids (BCAAs) Can't "LIV" without them • shared renal transporter

Leu

Leucine

BCAA • Essential

EnergyPurely KETOGENIC: one of only 2 (Lys + Leu)

TransportAll 3 BCAAs share the same transport protein in the renal collecting duct

Ile

Isoleucine

BCAA • Essential

EnergyBoth glucogenic AND ketogenic

TransportShares renal transporter with Leu and Val

Val

Valine

BCAA • Essential

DiseaseMaple syrup urine disease: can't break down BCAAs (BCAA dehydrogenase defect). Sweet-smelling urine, seizures, neurologic decline

EnzymeBranched-chain AA dehydrogenase needs 5 vitamins (same as pyruvate DH and alpha-ketoglutarate DH)

Metabolic Fate Summary

Purely Ketogenic (only 2)

Lysine and Leucine

Broken down into acetyl-CoA only. Cannot make glucose. Cannot do gluconeogenesis.

Both Glucogenic AND Ketogenic (4)

Phe, Ile, Thr, Trp 🔑PITT: Phe, Ile, Thr, Trp. Like Brad Pitt, can play any role (glucose or ketone).

Can break down into intermediates for either gluconeogenesis or ketogenesis.

Enzyme Recognition Cheat Sheet

Enzyme	Recognizes	Action
Chymotrypsin	Phe, Trp, Tyr (aromatics)	Cuts peptide bond to their right side
Trypsin	Lys, Arg (basic)	Cuts peptide bond to their right side
Serine proteases	Ser in active site	Trypsin, chymotrypsin, elastase, thrombin

Chymotrypsin

RecognizesPhe, Trp, Tyr (aromatics)

ActionCuts peptide bond to their right side

Trypsin

RecognizesLys, Arg (basic)

ActionCuts peptide bond to their right side

Serine proteases

RecognizesSer in active site

ActionTrypsin, chymotrypsin, elastase, thrombin

The GABA Connection

A 58-year-old man with decompensated cirrhosis is admitted in a confused state. Serum ammonia is 210 mcmol/L. His wife says "he just kept falling asleep." Which mechanism most directly links the elevated ammonia to his confusion?

The liver normally clears ammonia via the urea cycle. Failure opens the floodgates. NH4+ + alpha-ketoglutarate forms glutamate. Excess glutamate is converted to GABA by glutamate decarboxylase. GABA = inhibitory. The brain over-inhibits itself. Every coma linked to elevated ammonia (hepatic, uremic, DKA) converges on the same final pathway: NH4+ drives GABA up.

🧠 The GABA Connection: Mechanism Map

NH4+ + αKG → Glutamate → GABA ↑

Ammonium (NH4+) comes from urea and acid: NH3 + H+ = NH4+

Le Chatelier principle: pile up substrate on the left, drive the reaction right. More ammonia = more glutamate = more GABA.

GABA is inhibitory. When GABA rises, the CNS slows. The clinical pattern is always the same: patient gets confused, drowsy, then unresponsive.

►Liver failure: can't clear ammonia → NH4+ rises → glutamate rises → GABA rises → hepatic encephalopathy

►Kidney failure: can't clear urea → same pathway → uremic encephalopathy

►DKA: ketones are acidic → more acid drives more NH4+ → GABA rises → diabetic coma

From the Attending

Every coma with elevated ammonia runs through the same channel. Liver fails, ammonia rises, glutamate rises, GABA rises, patient fades. Know the bridge. If you can trace the nitrogen from liver failure to GABA in under 10 seconds, you own this concept.

Drug Chemistry: Acids, Bases, and Amino Acid Toxicology

Acidic Drugs (pKa < 7)

Want more absorption? Add acid: drug stays neutral, crosses membranes

Want to flush it? Add a base: drug gets charged, water-soluble, excreted in urine

Basic Drugs (pKa > 7)

Want more absorption? Add base: drug stays neutral, crosses membranes

Want to flush it? Add acid: drug gets charged, water-soluble, excreted

Board Translation

Neutral = fat-soluble = crosses membranes = bioavailable
Charged = water-soluble = stays in lumen or blood = excreted

Same pH as drug = keeps it neutral = more absorbed. Opposite pH = charges it = blocks absorption or promotes excretion.

💊

Aspirin

Acid

MechanismIrreversible COX-1 and COX-2 inhibitor: acetylates cyclooxygenase permanently

AbsorbedIn the stomach: low pH keeps aspirin neutral and fat-soluble for absorption

Overdose txGive a base (sodium bicarbonate): charges the acid, blocks reabsorption, urine excretion rises

Board trapReye syndrome: aspirin + viral illness in children → hepatic and cerebral damage. Never give aspirin to children with flu or chickenpox.

💤

Barbiturates

Acid

MechanismIncreases DURATION of chloride channel opening at GABA-A receptors (vs. benzos which increase frequency)

Mnemonic🔑Bar-DURATION: bars stay open all night (duration). Benzo-FREQUENCY: you see Ben frequently at short intervals. Barbiturates → Duration. Benzos → Frequency.

Overdose txGive a base: charges it, excretes it

⚠️

TCAs (Tricyclic Antidepressants)

Acid

Key drugAmitriptyline: drug of choice for chronic neuropathic pain

The problemTCAs have 6 simultaneous mechanisms. This makes overdose dangerously unpredictable.

Tap each mechanism to expand:

Blocks Reuptake

Blocks DA, NE, serotonin reuptake. All three rise. Can push BP UP.

Anticholinergic

Strongly anticholinergic. Hot, dry, flushed, dilated pupils. No sweating (sweat glands are the only sympathetic tissue that uses ACh). Board clue: tells anticholinergic from pure sympathetic.

Blocks Alpha-1

Alpha-1 blockade → vasodilation → BP drops. Same drug, same patient, BP can go up or down depending on which effect wins at that moment.

Blocks Na+ Channels

The lethal mechanism. Ventricular sodium channel blockade → widened QRS (>100ms) → fatal arrhythmia. Treat with IV sodium bicarbonate.

Blocks AV Node

Slows AV conduction → heart block, bradycardia. Can be paradoxical next to tachycardia from reuptake blockade.

Antihistamine

H1 blockade → sedation, weight gain. Explains the "sleepy and hungry" side effect.

⚡

Amphetamines

Base

Why baseAmphetamines have an amine group (NH2). Amines are basic. This is a direct amino acid chemistry connection.

Overdose txGive an acid (ammonium chloride): charges the base, blocks reabsorption, excreted

Alert patientGive acid orally (cola, OJ) while awaiting IV access

Rhabdomyolysis: The Myoglobin Problem

Why myoglobin destroys kidneys

Myoglobin is a very acidic protein with high affinity for renal tubular cells. After crush injury, it's tamponaded under the weight. The moment you lift the object, all of it floods the circulation and heads straight to the kidneys.

Bicarbonate gives myoglobin a negative charge → reduces renal bioavailability → kidneys excrete it instead of absorbing it. That is why bicarb must start before the object is lifted.

Step 1: Get IV access immediately

Step 2: Start sodium bicarbonate drip BEFORE lifting the object. This is non-negotiable.

Step 3: All myoglobin is tamponaded under the compression. Once lifted, it floods the circulation instantly.

Step 4: Lift the object. Bicarb is already protecting the kidneys.

Step 5: Monitor CK, creatinine, potassium (hyperkalemia is a secondary killer), and urine color (dark brown = myoglobinuria).

From the Attending

Start the bicarb before you lift the object. The myoglobin is waiting. The second that weight comes off, all that muscle protein floods the circulation. The kidney is first to fall. The clinical medicine will test the order of operations. Bicarb first. Lift second.

🎯 Board Walkthrough

6 original clinical vignettes · one at a time · never repeat · tap answers to reveal progressive teaching

VIGNETTE 1 OF 6

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