TBL 1: Amino Acids & Proteins

Essential Amino Acids

Phe, Val, Thr, Trp, Ile, Met, His, Leu, Lys

Nonpolar/Hydrophobic AAs

Glycine

Alanine (source of E for muscles)

Proline (tight turns)

Methionine (initiates protein synth)

Isoleucine

Leucine

Valine

Branched chain AAs

Isoleucine

Leucine

Valine

Nonpolar Aromatic AAs

Phenylalanine

Tyrosine

Tryptophan

Tryptophan is precursor of

serotonin, niacin (Vit B3) & melatonin

Polar Uncharged AAs

Serine, Threonine (undergoes phosphorylation)

Cysteine (disulfide bonds)

Glutamine (major ammonia carrier)

Asparagine

Tyrosine is precursor of

DOPA (—> melanin)

Dopamine

nor-epi

epi

thyroxine

Polar, Charged Acidic AAs

Glutamate & Aspartate (don’t cross BBB, dissociates to COO- at physiological pH)

Glutamate (essential for nitrogen homeostasis)

Polar, Charged Acidic AAs

Arginine & Lysine (bind to negatively charged DNA)

Histidine (—> histamine)

Histamine 1 Receptor

located on immune system cells

allergy inducer

antagonist = diphenhydramine

Histamine 2 Receptor

stomach acid inducer (via parietal cells)

antagonist = cimetidine

Ketogenic AA

Lysine

Leucine

Phenylketonuria (PKU)

CLASSIC defined by deficiency of which enzyme?

phenylalanine hydroxylase

converts phenylalanine to Tyrosine

Tetrahydrobiopterin (THB-) Responsive PKU

defined by defiency of which enzyme?

dihydrobiopterin reductase deficiency

converts DHB to THB

*more severe than classic bc THB cofactor to multiple enzymes

• responds to THB admin w/ sapropterin

Alkaptonuria

defined by deficiency of what enzyme?

Homogentisate 1,2-dioxygenase

converts Homogentisate to Ketogenic substrates

*—> ochronosis (staining) from gentisic acid build up

• presents later in life (40s-60s)

Albinism

defined by deficiency of what enzyme?

Tyrosinase

converts Dopamine to Melanin

Tyrosinemia Type I (HT1)

defined by dysfunction of what enzyme?

Fumarylacetoacetate hydrolase

converts Fumarylacetoacetate to Fumarate (ATP) & Ketogenesis product (ATP)

*Fumarylacetoacetate not stable and converts to succylacetone

• most common tyrosinemia

• more severe than HT2

• affects liver AND kidneys

• Nitisinone is a treatment option (+ low protein diet)

Tyrosinemia Type II (HT2)

defined by dysfunction of what enzyme?

Tyrosine aminotransferase (removes -NH2)

converts tyrosine to hydroxylphenylpyruvate

• affects liver

• photophobic

• eye & skin disorders

What are prions?

Example of disease from prions:

abnormal, pathogenic agents —> unfold secondary structure of body proteins

—> neurodegenerative disease

Ex. CJD

What is amyloidosis?

Examples?

group of diseases in which amyloid protein accumulates

Ex. Alzheimer’s Disease

Type 2 Diabetes

Creutzfeldt-Jakob disease (CJD)

prion disease

• primary protein sequence identical but structure of proteins altered

• use pt Hx to differentiate from AD

  • contaminated human growth hormone

  • corneal transplantation from diseased donor

• quick onset (sporadic)

• ataxia (loss of movement control)

• myoclonus (involuntary jerking)

• autopsy would reveal “vacuoles”

Alzheimer’s Disease (AD)

accumulation of abnormal beta-amyloid plaques & tau tangles

what is Tau?

protein that stabilizes microtubules in neuron axons

*in AD, too many phosphate groups attached to tau —> detach from microtubules

AD autosomal linked to mutations in which 3 genes?

1. APP

2. Presenilin 1 (PSEN1)

3. PSEN 2

What is APP?

protein membrane receptor that functions for axon formation, metal homeostasis, and cell survival

• also promotes synapse formation

to properly insert into membrane, APP must be cut by ____ into the membrane protein & ____

γ-secretase complex

Aβ40

What is PSEN?

mutation can lead to what?

catalytic subunit in γ-secretase complex

mutation —> produce Aβ42 instead (longer & harder to turn into AAs)

amyloid plaques are removed by what?

Apo E (apolipoprotein E)

• endocytosis lipoprotein particles into hepatocytes for metabolism and clearance

ApoE2

protective against AD but not v. good at removing plaques

ApoE3

not related to AD risk

ApoE4

strong genetic risk factor for LATE-ONSET AD

*symptoms in 60s

• ApoE4 mutation —> other isoforms unable to handle aggregate clearance

PSEN1 mutation

most common cause of early onset familial AD (EOFAD)

*youngest age of onset (30s-50s)

PSEN2 mutation

rare & highly variable penetrance (if pts develop symptoms)

wide age range (35-85)