Cellular GeneticsCellular Genetics

Fall 2006Fall 2006

Synthesis of Proteins and Synthesis of Proteins and the ERthe ER

Lysosomal Lysosomal enzymesenzymes

Membrane Membrane proteinsproteins

Secretory Secretory proteins proteins

Proteins are Proteins are polypeptides polypeptides

MacromoleculeMacromolecules composed of s composed of amino acids amino acids joined by joined by peptide bondspeptide bonds

Proteins have levels of Proteins have levels of structurestructure

The structure of The structure of protein protein molecules is molecules is dependent upon dependent upon the sequence of the sequence of the amino acidsthe amino acids

It is also It is also dependent upon dependent upon the the intermolecular intermolecular forces between forces between the amino acidsthe amino acids

ChaperonesChaperones

Chaperones are Chaperones are molecules that molecules that assist proteins assist proteins in the process in the process of attaining of attaining their final their final structurestructure

MutationsMutations

Mutations in the sequence of Mutations in the sequence of amino acids can result in amino acids can result in misfoldingmisfolding

Misfolding results in an Misfolding results in an abnormal shapeabnormal shape

Misfolded proteins are regarded Misfolded proteins are regarded as defective and are removed as defective and are removed by the ER and degradedby the ER and degraded

Misfolded proteins that are not Misfolded proteins that are not removed cause diseaseremoved cause disease

Proteins affectedProteins affected

Membrane channels( Cystic Membrane channels( Cystic fibrosis, Cl-1 channel)fibrosis, Cl-1 channel)

Receptors located on the Receptors located on the outside of membranes( FH – outside of membranes( FH – LDL receptor in LDL receptor in hypercholesterolemia)hypercholesterolemia)

Enzymes( Enzyme deficiency – Enzymes( Enzyme deficiency – lactase deficiency)lactase deficiency)

Enzyme and substrateEnzyme and substrate

Enzymes Enzymes dependent dependent upon the shape upon the shape of the active of the active site to bind the site to bind the substratesubstrate

( reactants)( reactants) No product will No product will

be formed be formed without the without the association of association of the Enzyme the Enzyme and substrateand substrate

Lactose intoleranceLactose intolerance

Lactose IntoleranceLactose Intolerance

Lactose intoleranceLactose intolerance

How prevalent is How prevalent is Lactose Lactose Intolerance? Intolerance?

About 70% of the About 70% of the world's population world's population just can't drink milk just can't drink milk or eat dairy or eat dairy products without products without getting an upset getting an upset stomach. stomach.

Lactose Intolerance Lactose Intolerance is a recessive is a recessive genetic disorder genetic disorder and happens most and happens most often in people of often in people of African, Asian and African, Asian and Mediterranean Mediterranean descent. descent.

SymptomsSymptoms

It is caused by a deficiency of It is caused by a deficiency of lactase, an enzyme needed to lactase, an enzyme needed to absorb and digest lactose absorb and digest lactose (milk sugar). (milk sugar).

Undigested lactose lingers in Undigested lactose lingers in the intestine. the intestine.

Fermentation occurs - creating Fermentation occurs - creating intestinal discomfort intestinal discomfort (abdominal pain, bloating, gas (abdominal pain, bloating, gas and diarrhea). and diarrhea).

Lactase enzymeLactase enzyme

LactaseLactase

The enzyme The enzyme lactase will lactase will break down break down lactose into lactose into glucose and glucose and galactosegalactose

ReactionReaction

Cystic fibrosisCystic fibrosis

Chloride Chloride channel in the channel in the plasma plasma membranemembrane

Affects the Affects the lining of the lining of the respiratory treerespiratory tree

CFTR – CFTR –

Cystic fibrosisCystic fibrosis

transconductance transconductance regulatorregulator

ABC transporterABC transporter

Requires ATPRequires ATP Moves chloride Moves chloride

across the across the membranes in membranes in the lungthe lung

LysosomesLysosomes

Used in Used in recyclingrecycling

Digestion of Digestion of complex complex molecules to molecules to form simpler form simpler moleculesmolecules

Secretory Secretory productsproducts

Developmental Developmental processesprocesses

Structure forms Structure forms from the Rough from the Rough endoplasmic endoplasmic reticulumreticulum

Acid interiorAcid interior CompartmentalCompartmental

ized so that it ized so that it does not does not rupturerupture

At least 40 At least 40 enzymes that enzymes that can be found in can be found in lysosomeslysosomes

Lysosomal Storage Lysosomal Storage DiseaseDisease

Fabry DiseaseFabry Disease

FabryFabry

Fabry disease is a Fabry disease is a lysosomal storage lysosomal storage disorder seen in disorder seen in one out of every one out of every 40,000 people. It 40,000 people. It is caused by a is caused by a deficiency in the deficiency in the enzyme alpha-enzyme alpha-galactosidase galactosidase which then results which then results in the body’s in the body’s inability to break inability to break down specific down specific fatty substances fatty substances called called globotriaosylceraglobotriaosylceramide (abbreviated mide (abbreviated GL-3 or Gb3). GL-3 or Gb3).

Hurler- SchieHurler- Schie

MucopolysaccharidosiMucopolysaccharidosis I is a lysosomal s I is a lysosomal storage disorder that storage disorder that is abbreviated MPS I is abbreviated MPS I and sometimes called and sometimes called Hurler syndrome, Hurler syndrome, Hurler-Scheie Hurler-Scheie syndrome, or Scheie syndrome, or Scheie syndrome. It is syndrome. It is caused by a caused by a deficiency in the deficiency in the enzyme alpha-enzyme alpha-iduronidase which is iduronidase which is needed to break needed to break down certain complex down certain complex sugars called sugars called glycosaminoglycans glycosaminoglycans (abbreviated GAGs (abbreviated GAGs and formerly called and formerly called mucopolysaccharides)mucopolysaccharides). .

MucolipidosisMucolipidosis

Lysosomal Lysosomal storage diseasestorage disease

Enzyme lackingEnzyme lacking MP3MP3 New treatmentNew treatment

Pamidronate Pamidronate Test with urine Test with urine

spot testspot test

PeroxisomesPeroxisomes

PeroxisomesPeroxisomes are are ubiquitous ubiquitous organellesorganelles in in eukaryoteseukaryotes that that function to rid the function to rid the cellcell of toxic substances. of toxic substances. They have a single They have a single membranemembrane that that separates their separates their contents from the contents from the cytosolcytosol (the internal (the internal fluid of the cell) and fluid of the cell) and that contains that contains membrane proteins membrane proteins critical for various critical for various functions, such as functions, such as importing proteins importing proteins into the organelles into the organelles

AdrenoleukodystrophyAdrenoleukodystrophy

Rare genetic diseaseRare genetic disease Neuromuscular degenerationNeuromuscular degeneration Demyelination of neuronsDemyelination of neurons Muscular atrophyMuscular atrophy Loss of hearing and speechLoss of hearing and speech

AdrenoleukodystrophyAdrenoleukodystrophy

Recent evidence suggests that Recent evidence suggests that a mixture of oleic acid and a mixture of oleic acid and euric acid, known as euric acid, known as "Lorenzo's Oil," administered "Lorenzo's Oil," administered to boys with X-ALD can reduce to boys with X-ALD can reduce or delay the appearance of or delay the appearance of symptoms. symptoms.

X-AldX-Ald

People with ALD accumulate People with ALD accumulate high levels of saturated, very high levels of saturated, very long chain fatty acids (VLCFA) long chain fatty acids (VLCFA) in the brain and adrenal cortex in the brain and adrenal cortex because they do not produce because they do not produce the enzyme that breaks down the enzyme that breaks down these fatty acids in the normal these fatty acids in the normal manner manner

Gene Location on XGene Location on X

ALD - TreatmentALD - Treatment

OilOil Adrenal Adrenal

hormoneshormones Bone Marrow Bone Marrow

transplanttransplant Stem Cell Stem Cell

transplanttransplant

Lorenzo’s OilLorenzo’s Oil