BIOCHEMISTRY FOR MEDICAL STUDENTS

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BIOCHEMISTY

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• Quick Learning
• Technique

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THE CELL STRUCTURE
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NUCLEUS

•     The nucleus houses the DNA (deoxyribonucleic
  acid) which stores genetic information for a
  cell. The DNA contains instructions for the
  production of the cell's proteins and for
  reproduction.
• To construct proteins, 1) The DNA is copied to
  messenger RNA (ribonucleic acid) in the process
  called transcription. 2) The mRNA goes to the
  ribosomes, 3) Either in the nucleus or in the
  endoplasmic reticulum, where the actual
  construction of the proteins takes place.   
  Structurally, the nucleus is composed of three
  main parts, the nucleolus, the nuclear envelope,
  and the chromatin.

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Nucleus of Cell
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Cromatin Structure

• Heterochomatin-Condensed/inactive
• Euchomatin-
• Loosely packed/ highly active

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Rough Endoplasmic Reticulum

• This is the site of Protein Synthesis

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Smooth Endoplasmic Reticulum

• This is the site of Steroidal Synthesis

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Amino Acid Basics

• Proteins are built up from amino acids which are
  linked by peptide bonds to form a polypeptide of
  defined sequence. Many proteins are folded into
  well defined globular shapes because the
  hydrophobic effect forces hydrophobic side chains
  along the polypeptide sequence to cluster
  together in a hydrophobic core. The folded
  protein is stabilized by a large number of weak
  interactions. There are 4 levels of organization,
  or structure, to a protein, going from the
  primary (1) structure (the amino acid sequence),
  via secondary (2) structure, tertiary (3, 3D)
  structure, to quaternary (4) structure in the
  case of multi-chain proteins. The amino acid side
  chains have a variety of chemical groups that
  make them particularly suitable for carrying out
  the numerous tasks they perform in the cells.

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Protein Structure/Function

• To a large extent, proteins are built up by
  ordered structures the secondary structure
  elements a-helices and b-pleated sheet. These
  arise when the same phi/psi angles are repeated
  over a number of residues and are stabilized by
  hydrogen bonds involving the main chain carbonyl
  oxygen and peptide nitrogen.
• Secondary structural elements are joined by loops
  or turns, and are often combined in particular
  ways called motifs that in turn are combined to
  generate functional protein domains.

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2nd Function of Proteins

• Oxygen is transported in mammals by hemoglobin
  and stored in muscles by myoglobin. Hemoglobin
  has allosteric properties which makes it suitable
  for picking up oxygen when the oxygen pressure is
  high (in the lungs) and release it when the
  oxygen pressure is low (in the muscles).

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Carbohydrates

• Carbohydrates are the most abundant biomolecules.
  Certain carbohydrates are staple of the human and
  animal diet, and the oxidation of carbohydrates
  is the central energy-yielding pathway.There are
  three major classes of carbohydrates
• 1) Monosaccharides, or simple sugars, consist
  of a single polyhydroxy aldehyd or ketone unit.
• 2) Oligosaccharides consist of short chains of
  monosaccharide units joined together with
  glycositic linkages.
• 3) Polysaccharides consist of long chains. Some
  polysaccharides, such as e.g. cellulose, have
  linear chains of monosaccharides , whereas
  others, glycogen for example, have branched
  chains.

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Fatty Acids

• Fatty acids have major physiologic roles, such as
  being building blocks of phospholipids and
  glycolipids (components of cell membranes),
  precursors of hormones and intracellular
  messengers, fuel molecules, etc. Because fatty
  acids are highly reduced, yielding 9 kcal/g after
  complete oxidation (twice as much as
  carbohydrates and proteins). Fatty acids can
  originate either in the diet or from de novo
  synthesis in the cytosol of cells. Fatty acid
  synthesis requires C atoms (as acetyl CoA) and
  reducing power as NADPH. Acetyl groups are
  translocated from mitochondria to the cytosol as
  citrate (though in ruminants acetate from the
  rumen is the main precursor of cytosolic acetyl
  CoA).

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Energy Yield

• 4/9/4
• Ideal Fat 10/10/10

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Carbohydrates

• 4 Kcal/g carbohydrate
• Monosacchideglucose fructose
• DisaccharidesLactose, maltose, sucrose
• Currently 46 of dietshould increase to 55 of
  diet

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Fats

• 9 Kcal/g
• Saturated 10
• Coconut and palm oil
• Monosaturated 10
• Olive and canola oil
• Polysaturated 10
• Soybean and Corn

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Protein

• 4 Kcal/g
• 20 amino acids
• Proteins from wheat, corn, rice, and beans have
  lower biological value than meat proteins
• NITROGEN BALANCE IS KEY
• Exwheat-lacks lysine
• Kidney beans lysine rich

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Carbohydrates
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Biochemistry

• Now we are biochemists
• The chemistry in living systems

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Carbohydrates

• Aldehydes or ketones
• Polyhydroxy compounds
• Important energy source in the body
• 4 cal/g
• Most important is glucose

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Classification

• Carbohydrates are classified according to size
• Monosaccharide a single polyhydroxy aldehyde or
  ketone unit.
• Disaccharide composed of two monosaccharide
  units
• Polysaccharide very long chains of linked
  monosaccharide units.
• Oligosaccharide- has between 3 10 units

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Classification
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Monosaccharide Classification

• Classified by whether the monosaccharide is an
  aldehyde (aldose) or ketone (ketose).
• Classified by the number of carbon atoms in the
  monosaccharide.

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Physical Properties

• Most are called sugars because they taste sweet.
• Because of the many OH groups, they form
  hydrogen bonds with water molecules and are
  extremely water soluble.
• Most are solids at room temperature because of
  H-bonding between them

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• All monosaccharides with at least five carbon
  atoms exist predominantly as cyclic hemiacetals
  and hemiketals.
• A Haworth structure can be used to depict the ?
  and ? anomers of a monosaccharide.
• Anomers are stereoisomers that differ in the 3-D
  arrangement of groups at the anomeric carbon of
  an acetal, ketal, hemiacetal, or hemiketal group.
  

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• Six-membered pyranose ring system

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Five-membered furanose ring system
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• Monosaccharide Reactions, cont.
• A reducing sugar can be easily oxidized.
• All monosaccharides are reducing sugars.
• Benedicts reagent tests for the presence of
  reducing sugars
• Reducing sugar Cu2 ? oxidized compound
  Blue Cu2O orange-red
  precipitate

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• Monosaccharide Reactions, cont.
• The OH groups of monosaccharides can behave as
  alcohols and react with acids (especially
  phosphoric acid) to form esters.

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• Important Monosaccharides
• Ribose and Deoxyribose Used in the synthesis of
  DNA and RNA.
• Glucose Most nutritionally important
  monosaccharide Sometimes called dextrose or
  blood sugar
• Galactose A component of lactose (milk sugar)
• Fructose The sweetest monosaccharide Sometimes
  called levulose or fruit sugar

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• Disaccharides
• Two monosaccharide units linked together by
  acetal or ketal glycosidic linkages.

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• Important Disaccharides
• Maltose Two glucose units linked ?(1?4) Formed
  during the digestion of starch to glucose
• Reducing sugar
• Lactose Galactose and glucose units linked
  ?(1?4) Found in milk
• Reducing sugar
• Sucrose Fructose and glucose units Found in
  many plants (especially sugar cane, sugar
  beets) Not a reducing sugar

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Maltose in solution
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• Polysaccharides
• StarchA polymer consisting of glucose units Has
  two forms
• Unbranched amylose
• Branched amylopectin
• Complexes with iodine to form a dark blue color

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Polysaccharide Structure
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The Structure of Amylose
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Amylopectin Structure
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• Polysaccharides, cont.
• Glycogen (animal starch) a polymer of glucose
  units.Used to store glucose, especially in the
  liver and muscles.Structurally similar to
  amylopectin with ?(1?4) and ?(1?6) linkages, but
  glycogen is more highly branched.

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• Polysaccharides, cont.
• Cellulose A polymer of glucose units The most
  important structural polysaccharide Found in
  plant cell walls Linear polymer like amylose,
  but has ? (1?4) glycosidic linkages. Not easily
  digested, a constituent of dietary fiber.

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Cellulose Structure
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Polysaccharide linkages
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Lipid Metabolism
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Lipids

• Important source of energy
• 9 cal/g
• Used to store energy in the body
• 30-40 day supply

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Blood Lipids

• Lipids are non-polar and therefore do not like
  the aqueous blood environment
• Complex themselves with proteins to form
  lipoprotein aggregates called chylomicrons
• Chylomicrons are further processed by the liver
  to form lipoproteins we are familiar with

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Lipoproteins

• Classed based on density
• Lipids are less dense than proteins
• So, lipoproteins with a higher proportion of
  lipids are less dense

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Chylomicron
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Lipoproteins
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Lipid Digestion

• Triglycerides are hydrolyzed to glycerol, fatty
  acids, and monoglycerides
• Phosphoglycerides are hydrolyzed to their
  individual components
• These smaller molecules are absorbed in the
  intestines
• Blood lipids follow similar pattern to blood
  sugar levels and are highest after a meal

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Fat Mobilization

• When energy is required messengers are sent out
  to interact with adipose tissue
• Epinephrine stimulates triglyceride hydrolysis in
  the process of fat mobilization
• Fatty acids are then transported to the tissues
  that need the energy

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Fat cells
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Fat Mobilization, contd

• Some cells cannot use fats for energy, brain
  cells and red blood cells
• Other cells preferentially use lipids for energy
  to conserve the supply for the other cells,
  muscles and liver
• They break fatty acids down for energy

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Glycerol Metabolism

• Glycerol is converted into dihydroxyacetone
  phosphate in two reactions

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Fatty Acid Oxidation

• Fatty acid must be activated before it can be
  metabolized
• Passes through mitochondrial membrane
• Requires energy in the form of ATP
• Fatty acid then enters the fatty acid spiral and
  undergoes b-oxidation

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Lipids contd

• Fig. 14.6
• Fatty acids are transported across the inner
  mitochondrial membrane in the form of acyl
  carnitine.

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Fatty acyl refers
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b-Oxidation
The b-carbon is oxidized to a ketone in a series
of four reactions in the mitochondrion
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Fatty Acid Oxidation
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b-Oxidation, contd

• The final step breaks the chain between the a and
  b carbon atoms by reaction with coenzyme A
• A new fatty acyl CoA is formed that is two carbon
  atoms shorter then original
• Fatty acid spiral continues until all carbons are
  used
• Fatty acids are broken down two carbons at a time

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Energy Produced

• Every two carbon unit produces one acetyl CoA
• Every two carbon unit except the last has to go
  through the fatty acid spiral to produce the
  acetyl CoA
• Every spin through the fatty acid spiral produces
  1 FADH2 and 1 NADH

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Energy Production, contd

• Each acetyl CoA has the potential to enter the
  citric acid cycle and produce 1ATP, 3NADH, and
  1FADH2
• The NADH and FADH2 then go to the electron
  transport
• NADH ? 2.5ATP
• FADH2 ?1.5ATP

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Energy produced
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Question for You

• How many molecules of ATP are produced by the
  complete oxidation of palmitic acid, (16C) to
  carbon dioxide and water?

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Answer

• 16 carbon atoms ? 8 acetyl CoA
• 7 fatty acid spirals ? 7NADH 7FADH2
• Activation step ? -2ATP
• Acetyl CoA ? 10ATP
• Overall (8 x 10) (7 x 2.5) (7 x 1.5) -2
• 106ATP

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Ketone Bodies

• Under certain conditions (e.g. fasting and
  diabetes) an imbalance between carbohydrate and
  fatty acid metabolism occurs and more acetyl CoA
  is produced by fatty acid oxidation than can be
  processed by the citric acid cycle.
• Glycolysis is essentially shut down and
  oxaloacetate is used in gluconeogenesis
• The citric acid cycle slows down and acetyl CoA
  builds up in the body
• The body synthesizes ketone bodies to rid itself
  of excess acetyl CoA

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Ketone Bodies
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Ketone Bodies
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Ketone Bodies

• Are oxidized to meet energy needs
• Excess amounts causes a change in blood pH as two
  are acids, ketoacidosis
• Diabetes can cause this as a lack of insulin
  means cells do not take glucose in and thus fatty
  acid oxidation is used as the energy source and
  causes the build-up of ketone bodies

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Fatty Acid Synthesis

• Excess nutrients are stored rather than excreted
• Excess is converted first to fatty acids and then
  to body fat
• Most body fat production is in the liver, adipose
  tissue and mammary glands
• Biosynthesis of fatty acids is not the exact
  opposite of degradation

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Fatty Acid Synthesis, contd

• Occurs in the cytoplasm
• Acetyl CoA is moved from the mitochondrion to the
  cytoplasm
• Fatty acid synthetase system makes the fatty
  acids two carbons at a time
• Requires large amounts of energy which is then
  stored in the synthesized fatty acid

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Lipids contd

• Fig. 14.10
• The citrate-malate-pyruvate shuttle system for
  transferring acetyl CoA from a mitochondrion to
  the cytosol.

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• Liver is most involved in fatty acid synthesis
• Can modify fatty acids by adding/ removing carbon
  atoms
• Can also reduce or oxidize
• Glucose ? fatty acids
• Fatty acids cannot ? glucose (lack the enzyme for
  acetyl CoA ? pyruvate)

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Lipids contd

• Fig. 14.13
• Overview of the biosynthetic pathway for
  cholesterol synthesis.

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Proteins
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Proteins

• Made up of amino acids
• Have amino group, C-N
• Have acid group, COOH
• 20 amino acids
• All but one are chiral
• All L-amino acids

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Functions

• Catalysts
• Structural component
• Storage
• Protection
• Regulation
• Movement
• Transport
• Nerve impulse transmission

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Amino Acids

• Called a-amino acids as amino group is on alpha
  carbon atom
• All except glycine are chiral
• Classified according to type of R group
• Non-polar/ Polar
• Acidic/ Basic

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Abbreviations and Codes

• Leucine L, Leu
• Lysine K, Lys
• Methionine M, Met
• Phenylalanine F, Phe
• Proline P, Pro
• Serine S, Ser
• Threonine T, Thr
• Tryptophan W, Trp
• Tyrosine Y, Tyr
• Valine V, Val

Alanine A, Ala Arginine R, Arg Asparagine N,
Asn Aspartic acid D, Asp Cysteine C,
Cys Glutamine Q, Gln Glutamic Acid E,
Glu Glycine G, Gly Histidine H, His Isoleucine I,
Ile
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Essential Amino Acids

• Lysine
• Leucine
• Isoleucine
• Histidine
• Methionine
• Phenylalanine
• Threonine
• Valine
• Tryptophan
• Arginine, only in children

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Peptides

• Connected by amide bond
• Now called a peptide bond
• Always put free N-group on left and free acid
  group on right

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Proteins

• May be simple or complex
• Complex proteins have an extra non-protein bit
• Non-protein bit is called prosthetic group
• Protein is inactive without prosthetic group

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Protein Shapes

• Fibrous proteins long rod-shaped or stringlike
  molecules that intertwine to form fibers
  (collagen, elastin, keratin).
• Globular proteinssphericalshaped proteins that
  form stable suspensions in water, or is water
  soluble (hemoglobin, enzymes).
• Based on water solubility

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Some Common Fibrous and Globular Proteins
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Myoglobin

• Fig. 20.4
• The primary structure of human myoglobin.

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Biochemically Important Small Peptides

• Small peptide hormones, oxytocin and vasopressin
• Both are nonapeptides
• Amino acids at spots 3 and 8 are different
• Oxytocin regulates uterine contractions and
  lactation
• Vasopressin regulates water excretion by kidneys
  and blood pressure

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Cont

• Enkephalins are pentapeptide neurotransmitters
  produced by the brain
• They bind to receptor sites to reduce pain
• Also play a role in the natural high runners
  get at the end of a long run
• Morphine and codeine bind to the same receptor
  sites as enkephalins

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And theres more

• Small peptide antioxidants
• Glutathione, Glu-Cys-Gly
• Protects cells from oxidizing agents

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Protein Structure, 50 a/a

• Four levels of structure
• Primary Amino acid sequence
• Secondary a-helix or b-sheet
• Tertiary How one chain folds up
• Quaternary How more than one chain folds up

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Protein Structure
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Protein Structure Primary

• Amino acid sequence
• Held together by peptide bond
• Also determines the secondary structure of the
  protein
• Not affected by denaturation
• Very stable covalent bond holds it together

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Protein Structure Secondary

• a-helix
• b-sheet
• Hydrogen bonding holds it together
• Depends on amino acid residues present

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a-helix
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b-Sheet
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Secondary Structure
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Protein Structure Tertiary

• A single chain folds up
• Hydrogen bonding
• Disulfide bonding
• Salt bridges
• Hydrophobic interactions

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Tertiary Interactions
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Disulfide Bond Formation
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Myoglobin, tertiary structure
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Insulin

• Fig. 9.11
• Human insulin, a small two-chain protein, has
  both intrachain and interchain disulfide linkages
  as part of its tertiary structure.

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Protein Structure Quaternary

• How two or more chains fold up together
• Hydrogen bonding
• Salt bridges
• Disulfide bonds
• Hydrophobic interactions

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Hemoglobin
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a-Keratin
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Collagen
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Collagen

• Most abundant protein in humans, 30
• Major structural material
• Tendons
• Ligaments
• Blood vessels
• Skin
• Bones and teeth

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Collagen Content
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Protein Denaturation

• Break 2o, 3o, and 4o structure only
• Does not affect 1o structure
• Protein is unfolded
• Native conformation is changed
• Protein is inactivated
• May sometimes be renatured

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Denaturation
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Protein Hydrolysis

• Breaks peptide bond
• Peptide bond is very stable so need heat, and
  acid/base, or the use of an enzyme

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ALCOHOL

• 7 Kcal/g

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Enzyme activity 1
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Energy Transition
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Michaelis-Menton
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Biochemical Energy Production
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Metabolism

• Sum of all biochemical reactions that take place
  in a living organism
• In 40 years we consume 6 tons of solid food and
  10,000 gallons of water
• Catabolism break-down of larger molecules into
  smaller ones
• Anabolism Build-up, smaller molecules make
  bigger ones

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Metabolism
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Cell Structure

• Prokaryotic cells have no nucleus, bacteria
• Eukaryotic cells have nucleus, organelles, and
  are much bigger (1000X) than bacterial cells
• Cell walls in eukaryotic (plant cells)
• We are eukaryotic

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Cell Structure and Metabolism
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Inside a cell

• Cytoplasm water based material of a eukaryotic
  cell
• Organelle minute structure that carries out a
  specific cellular function
• Cytosol Water based fluid part of the cytoplasm

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Organelles

• Lysosome Contains hydrolytic enzymes needed for
  repair, rebuilding and degradation
• Proteins ? amino acids
• Polysaccharides ? monsaccharides
• Destroy bacteria and viruses

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Organelles, Cont

• Mitochondrion Responsible for the generation of
  energy
• ATP synthase complexes on cristae of inner
  membrane

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Mitochondrion
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Intermediate Compounds With Nucleosides

• Adenosine phosphates, ATP, ADP, AMP

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Contd

• Hydrolysis of the phosphate ester bonds in ATP
  yields energy
• Bonds are reactive and are called strained
  bonds
• ATP is our unit of currency for energy

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ATP Hydrolysis
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ATP
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Flavin Adenine Dinucleotide, FAD, FADH2

• Coenzyme required in many redox reactions
• Comes from flavin and ribitol, the vitamin
  riboflavin
• This is then attached to ADP

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Nicotinamide Adenine Dinleotide, NAD

• Coenzyme required in redox reactions
• Has nicotinamide, B vitamin as part of structure
• Also attached to ADP

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FAD
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Types of Reactions for FAD
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NAD Reactions
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Reaction Types
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Coenzyme A

• Derived from a B vitamin, pantothenic acid
• Active part is the SH group and often abbreviated
  CoA-SH
• Get a thioester bond

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Coenzyme A
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Overview
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High Energy Phosphate Compounds

• Has a greater free energy of hydrolysis than that
  of a typical compound
• Easily broken bonds so the energy absorbed by
  bond breaking is much less than that of bond
  formation in the products
• Greater than normal electron-electron repulsive
  forces are the cause of the bond strain

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Overview of Biochemical Energy Production

• Energy needed to run the body is derived from
  ingested food

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Contd

• Multi-step process involving several catabolic
  pathways
• There are four stages in energy production
• Digestion
• Acetyl group formation
• Citric acid cycle
• Electron transport chain and oxidative
  phosphorylation

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Stage I Digestion
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Stage IIAcetyl Group Formation
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Stage III Citric Acid Cycle
Hans Adolf Kreb
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Citric Acid Cycle
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Citric Acid Cycle

• Stage III in the oxidation of fuel molecules
• Key intermediate is citric acid
• Also called Krebs cycle
• Also called tricarboxylic acid cycle
• Principal process for generation of reduced
  coenzymes, NADH and FADH2
• Occurs in the matrix of the mitochondrion

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Citric Acid Cycle

• Starts and ends with the same four carbon
  molecule, oxaloacetate
• Addition of Acetyl CoA gives a six carbon
  molecule, citric acid
• Two molecules of CO2 are produced, thus returning
  to the four carbon molecule
• Water is required also

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Citric Acid Cycle, contd

• Acetyl CoA is the fuel
• Depends on adequate supply of NAD and FAD,
  supplied form electron transport chain
• Four oxidation-reduction reactions produce three
  NADH, and one FADH2
• One GTP also produced

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Citric Acid Cycle

• Overall reaction
• Several redox reactions involving coenyzmes
• Hydration
• Condensation

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Regulation of the Citric Acid Cycle
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Citric Acid Cycle Regulation

• There are three main points of regulating citric
  acid cycle activity
• Citrate synthetase the first step of the cycle
  is inhibited by ATP and NADH and activated by
  ADP.
• Isocitrate dehydrogenase the third step of the
  cycle is inhibited by NADH and activated by ADP.
• Alpha-ketoglutarate dehydrogenase the fourth
  step of the cycle is inhibited by succinyl CoA,
  NADH, and ATP.

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Electron Transport Chain

• Series of reactions in which protons and
  electrons from the oxidation of foods are used to
  reduce molecular oxygen to water.
• NADH and FADH2 produced in citric acid cycle
  supply hydrogen ions and electrons to combine
  with oxygen to form water

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Electron Transport Chain

• Occurs in inner mitochondrial membrane
• Series of reactions
• Electrons from the reduced coenzymes are passed
  assembly line fashion from one electron carrier
  to the next
• The electrons finally combine with oxygen to form
  water

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ETC

• As the electrons pass along the carriers they
  lose some energy with each transfer and this
  energy is used to make ATP in oxidation
  phosphorylation
• Four protein complexes involved

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Electron Transport Chain
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Oxidative Phosphorylation

• Biochemical process where ATP is synthesized from
  ADP as a result of the transfer of electrons and
  hydrogen ions from NADH or FADH2 to oxygen
  through the electron carriers in the electron
  transport chain
• Coupled reactions are pairs of biochemical
  reactions that occur concurrently where energy
  produced by one reaction is used in the other
  reaction

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Chemiosmotic Hypothesis

• Theory that a proton flow across the inner
  mitochondrial membrane during the electron
  transport chain provides energy for the
  production of ATP
• This proton pump causes the formation of ATP by
  F1 -ATPase.

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Proton Pump
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Step 1 Proton gradient is built up as a result
of NADH (produced from oxidation reactions)
feeding electrons into electron transport
system.
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Electrons are transferred from electron carriers
to the Electron transport chain, involving many
enzyme complexes.
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Step 2 Protons (indicated by charge) enter
back into the mitochondrial matrix through
channels in ATP synthase enzyme complex. This
entry is coupled to ATP synthesis from ADP and
phosphate (Pi)
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ATP Production

• NADH ? NAD gives 2.5 ATP from ADP
• FADH2 ? FAD gives 1.5 ATP from ADP
• Acetyl CoA ? 10 ATP
• 3NADH ? 7.5ATP
• 1FADH2 ? 1.5ATP
• 1GTP ? 1ATP

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Overview of CAC and ETC
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Pentose Pathway
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Non-Oxidative Stage of Pentose Pathway
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Krebs Pneumonic

• Can
• Intelligent
• Karen
• Solve
• Some
• Foreign
• Mafia
• Operations

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Krebs Cycle  or Sometimes called the TCA Cycle
Krebs cycle occurs in the matrix of the
mitochondria. This is a series of reactions
that occur in a cycle as the name indicates.
Enzymes strip off the CoA  from acetyl CoA and
combine the acetyl...the two carbon fragment...
to a four carbon molecule in the cycle. Two
redox reactions produce two CO2, two NADH and one
ATP. Two more redox reactions produce one FADH2
and a an additional NADH Relating products of
Krebs cycle to one glucose moleculeEach turn of
the cycle utilizes one pyruvate or 1/2 of a
glucose molecule. This means we must consider the
cycle turning twice for each glucose.With two
turns of the cycle the following are produced per
glucose molecule. Two ATP Two FADH2 Six NADH

• KREBS CYCLE

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PROTEIN SYNTHESIS
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Sterol Biosynthesis
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Oxidative Phosporylation
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Consider the Weak Acid s

• HA ltgt H A-

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pH

• pH pKa log A-
• HA

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ACID BASE H20C02ltgtH2CO3ltgtHCO3H
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ANION GAP

• Na K CL HCO3

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DNA Pol B
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DNA replication-synthesis

• G1, S, G2, (interphase)
• M, (mitosis)
• Muscles, nerves, stay in O

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Transcription

• Develop mRNA
• Devoped as precursor (HETEROGENOUS NUCLEAR RNA)
• IN NUCLEUS---
• LOOK AT PREVIOUS SLIDE

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SAM

• SAM is the methyl donor man
• Methyl cap is at 5 end (LEFT)
• Poly-A-tail is at 3 end (right)
• INTRONS ALWAYS IN BETWEEN EXONS
• INTRONS STAY IN NUCLEUS
• Splicing cuts out introns and fuses EXONS to get
  sequenced by
• (SPLICASOMESNURPS)
• ALL HAPPENS IN NUCLEUS

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mRNA
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Translation

• Need tRNA and rRNA
• In cytoplasm

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Nucleic Acid

• Composed of Nucleotides
• BASE
• SUGAR
• PHOSPHATE
• If Remove Phosphate it is a nucleoside
• Difference in bases are purine and pyrmidines
• Purines are BIG ( ADENINE and GUANINE)
• Pyrimidine are small(C, U, T, bases U in RNA
  and T in DNA)
• Changes T into U , by removing amine group by
  deaminase
• Cytosine is the most highly Methylated- Turns
  genes off in that area of the chromosomesto turn
  them on must demethylate

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Linkage

• Nucleotides linked together by covalent
  phosphodiaster bond
• The one end is 5 and the other end is 3
• Always Read from 5 to 3left to right
• This happens in all except some virus like dsDNA
• CODON IS 3 nucleotides (AUG. UAA.)
• BASE PAIRING BY HYDROGEN BONDS
• A-?T
• C-?G
• THIS IS ALSO CALLED HYDRIDIZATION-anti-parallelmu
  st run in opposite direction

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Synthesis

• DNA or RNA polymerases, synthesize 5-3 by
• Copy template in 3-5
• This is complementary base pairing
• 3 EXONUCLEASES REMOVE FROM END
• This is really important in DNA synthesis
  proof-reading, ONLY HAPPENS IN DNA polymerases

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RNA PROTEIN SYNTHESIS

• Starts protein synthesis at AUG, nucleotides
  added to 3 end, Shein-Delvarno-Sequence (just a
  ribosomal binding site before AUG)
• Left to right----downstream
• TATA -25 Promotor is start site and binding
  for RNA polymerase----(1 START SITE)
• STOP IS STEM LOOP STRUCTURE
• Operon is a set of genes being transcribed,
  influenced by the promotor
• RNA CODING STRAND ALWAYS 5-3 (POLY-A- TAIL)
• Protein is always made Amino to Carboxyl
• RNA stop protein synthesis
• UAA (you are alien)
• UGA (your going away)
• UAG (you are gone)

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PROKARYOTES Bacteria

• Transcription and translation both happen in
  cytoplasm
• Because no nucleus in Bacteria

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INSULIN
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Structure of Insulin

• Insulin is composed of 51 amino acid composed in
  a polypeptide chains, designated A B.
• Insulin is either Synthesized from Porcine
  Insulin or Synthesized from recombinant DNA

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Insulin Receptor
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Regulation of Insulin

• STIMULATION
• Glucose- The beta cells are the most important
  glucose sensing cells in the body. The ingestion
  of glucose or carbohydrate rich meals leads to a
  rise in blood glucose which is a signal for
  insulin release
• Amino Acids- Ingestion of protein causes a
  transient rise in plasma amino acids levels which
  in turn induces an immediate secretion of insulin
• Gastrointestinal Hormones-the intestinal peptide
  secretin , gives an anticipatory rise to insulin
  levels in the portal vein before there is an
  actual rise in blood glucose
• Glucagon-Glucose stimulates the secretion of
  insulin and inhibits the release of glucagon.
  Type I diabetes where B-cell destruction removes
  the inhibitory influence of insulin on glucagon,
  Many of the symptoms of the disease are due to
  unrestrained activity of glucagon on target
  tissue

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Regulation of Insulin

• Inhibition
• Epinephrine-the catachol which is secreted by the
  adrenal medulla in response to immediate stress,
  trauma, or extreme exercise. It has direct effect
  on energy metabolism, causing rapid mobilization
  of energy yielding fuels of glucose from the
  liver, fatty acids from adipose tissue. Thus,
  epinephrine can override normal glucose
  stimulated release of insulin.
• Cortisol GH These hormones usually play a role
  in long-term maintenance, rather than short term
• Normally, cortisol levels rise during the
  early morning hours and are highest in midmorning
  (about 8 a.m.). They drop very low in the evening
  and during the early phase of sleep.

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INSULIN RECEPTOR leads to many diseases
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Glucagon

• Glucagon binds to high-affinity receptors on the
  cell membrane of the hepatocyte.
• Glucagon binding results in activation of
  adenylate cyclase in plasma membrane
• This causes a rise in cAMP, a second messenger,
  which in turn activates cAMP dependent protein
  kinase and increases the phosphorylation.
• This cascade is presented for the case glycogen
  degradation.

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Lipoproteins
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Cholesterol Intermediates

• "A Hot Momma Is Good For Sex, Love, and
  Cuddling."A-Acetyl CoAH-HMG CoAM-Mevalonic
  acidI-Isopentenyl pyrophosphateG-Geranyl
  pyrophosphateF-Farnesyl pyrophosphateS-Squalene
  L-LanosterolC-Cholesterol

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Chylomicrons-VLDL

• Intestinal Mucosa secrete TG-Rich chylomicrons
  (produced primarily from dietary lipids)
• Liver secretes TG rich very low density
  lipoprotein particles

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TG-Breakdown

• Extra-cellular lipoprotien lipase, activated by
  apo CII degrades TG in chylomicrons and VLDL
• Chlyomicron remnant travels via the vasculature
  and binds to specific receptors in liver where
  they are endocytosed

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IDL-LDL

• IDL-LDL binds to receptors on extra-hepatic
  tissues (and on Liver), where they are endocytosed

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Cellular uptake and degradation of LDL

• LDL receptors are negatively charged
  glycoprotiens molecules that are clustered in
  pits on cell membraneacts in Type II
  hyperbetalipoproteinemia
• After binding, the LDL are internalized as intact
  particle by endocytosis
• The vesicles containing LDL rapidly loose its
  Clathrin Coat and fuse with similar vesicles
  called ENDOSOMES
• The pH of the endosomal falls(due to a proton
  pump of endosomal ATPase, allowing separation of
  LDL from receptors
• The CURL is then form-Compartment for Uncoupling
  of Receptor and Ligand

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TYPE I

• Type I Familial Hyperchylomicronemia
• Massive fasting hyperchylomicronemia even after
  following normal dietary fat intake
• Deficiency of lipoprotien lipase or deficiency of
  normal apoprotein CII rare
• Type I is not associated with an increase in
  coronary heart disease
• Treatment low fat diet-No drug therapy

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Type IIA Familial Hyperbetaprotienemia

• Elevated LDL, with normal VLDLs level due to a
  block in LDL degradation, therefore increase
  serum cholesterol but normal triacylglyerol
• Caused by a decrease number of LDL receptors
• Ischemic Heart disease is greatly accelerated
• TX Low cholesterol/ Low Fat diet
• Heterozygotes-Cholestyramine or Colestipol, and
  Lovastatin or mevastatin
• Homozygotes-As above, plus niacin

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Type II B Familial Combined (mixed)
Hyperlipidemia

• Similar to IIA, except VLDL is also increased,
  resulting in elevated serum triacylglyerol as
  well as cholesterol
• Relatively common
• TxDietary restriction as above, low cholesterol,
  fat and no alcohol
• Similar to IIA, except heterozygotes also receive
  Niacin

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Type III Familial Dysbetalipoproteinemia

• Serum Concentrations of IDL are increased
  resulting in increasing triacyglyerol and
  cholesterol
• Cause is either overproduction or
  underutilization of IDL, perhaps due to mutant
  apoprotien
• Xanthomas and accelerated coronary and
  peripheral resistance develop by middle age
• TX-Weight reduction, Dietary restriction of
  cholesterol and alcohol
• Drug therapy includes niacin, and clofibrate (or
  gemfibrizol), or lovastatin (or mevastatin)

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• Type IV Familial
  Hypertriglyceridemia
• VLDL are increase, while LDL level as are normal
  or decreased, resulting in normal to elevated
  cholesterol, and greatly elevated circulation
  triacylglycerol
• Cause is either overproduction or decreased
  removal of VLDL in serum
• This is relatively common disease. It has few
  clinical manifestations other than accelerated
  ischemic heart disease
• Weight reduction is of primary
  importance-Dietary restriction of controlled
  carbohydrate, modified fat, low alcohol
  consumption
• If necessary, drug therapy includes niacin and
  or gemfibrizol (or Clofibrate), lovastatin or
  mevastatin

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Type V Familial Mixed
Hypertriglyceridemia

• Serum VLDL and Chylomicroms are elevated, LDL is
  normal or decreased. This results in elevated
  cholesterol and greatly elevated triacylglycerol
• Cause is either increased production or decreased
  clearance of VLDL and chylomicrons
• TX Weight reduction is important. Diet should
  include protein, low fat, controlled carbohydrate
  and NO ALCOHOL.
• Drug therapy include niacin, Clofibrate and/or
  Gemfibrizol , or lovastatin (or mevastatin)

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KETONES

• Ketones are substances the body produces when
  it breaks down fats for energy (metabolism).
  Normally, the body obtains energy from sugars
  (carbohydrates), but if a person's diet does not
  include enough sugars to supply the body with
  energy, or if the body cannot use sugars
  properly, it will break down stored fat and
  produce ketenes (a process called ketogenesis).
• If large amounts of ketones accumulate in the
  blood, a condition called ketosis may occur.
  Ketosis occurs most often in people who have
  poorly controlled type 1 diabetes. In type 1
  diabetes, the body lacks insulin to use sugars
  properly. To obtain energy from sugars, people
  with type 1 diabetes must inject insulin so their
  bodies can obtain energy the normal way, from
  sugars. If a person with diabetes does not take
  enough insulin, his or her body will have to
  break down fat for energy.

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Storage Diseases

• Glycogen Storage
• Type I- Von Geirkes
• Type II- Pompes
• Type V- McCardles
• Mucopolysacchridosis
• Scheies Syndrome (MPS I S)
• Hurlers Syndrome (MPS I H)
• Hunters Syndrome (MPS II)
• Sanfillipos Syndrome (MPS III) Types A-DSlys
  Syndrome (MPS VII)
• Glycospingolipids (sphingolipidosis) gangliosides
• GM 1
• Tay-Sachs
• Metachromatic Leukodystophy
• Fabrys Disease
• Neiman Pick Disease
• Farbers Disease

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Glycogen Storage Diseases

• Type I Von-Gierkes
• Glucose-6-Phosphatase Deficiency
• Affects liver, kidney, and intestine
• Fatty liver, hepatomegaly
• Severe Fasting HYPOglycemia
• Normal Glycogen structure
• NOTE In Von Geirkes the only source of glucose
  is food

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Glycogen Storage Diseases

• Type II-Pompes Disease
• (Lysosomal Alpha-Glucosidase Deficiency)
• Alpha 1-4 glucosidase (ACID MALTASE)
• Inborn lysosomal enzyme defect
• Generalized (LIVER, HEART, MUSCLE)
• EXCESSIVE GLYCOGEN CONCENTRATION-found in
  cytosomal vacuoles
• Normal blood sugar levels
• SEVERE CARDIOMEGALY
• Early death occurs
• Normal Glycogen Structure

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Glycogen Storage Diseases

• Type V- McArdles Syndrome
• (Glycogen Phosphorylase Deficiency)
• Temporary weakness and cramping after exercise
• No rise in blood lactate during exercise
• Myoglobinuria in later years
• Fair to good prognosis
• High level of glycogen in Muscle
• No ATP synthesis?no co A?no TCA cycle

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Mucopolysacchridosis

• Scheies Syndrome (MPS I S)
• Alpha-L-Iduronidase Deficiency
• Corneal Clouding, stiff joints, aortic valve
  disease, normal intelligence and life span
• Degradation of dermatan sulfate and heparan
  sulfate

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Mucopolysacchridosis

• Hurlers Syndrome (gargoylism) (MPS I H)
• Alpha-L-Iduronidase Deficiency
• Corneal Clouding, Mental retardation, Dwarfing,
  Coarse Facial Features
• Degradation of Dermatan Sulfate and Heparan
  Sulfate Affected
• Deposition in coronary artery leads to ischemia
  and early death

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Mucopolysacchridosis

• Hunters Syndrome (MPS II)
• Iduronate sulfatase deficiency
• X-linked
• Wide Range of Severity-No corneal Clouding, but
  physical deformity and mental retardation is mild
  to severe
• Degradation of dermatan sulfate and heparan
  sulfate

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Mucopolysacchridosis

• Sanfilippos (MPS III) Type A-D
• Four enzyme steps are necessary for removal of
  N-sulfated or N-acetylated glycoaminoglycan
  residues from heparin sulfate
• Type A-Heparan sulfamidase defiency
• Type B-N-Acetylglucosamidase deficiency
• Type C N-Acteyltranferase deficiency
• Type D N Acetylglucosamine deficiency
• SEVERE NERVOUS SYSTEM DISORDERS, MENTAL
  RETARDATION

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Mucopolysacchridosis

• Slys Syndrome (MPS VII)
• B-Glucuronidase deficiency
• Hepatosplenomegaly
• Degradation of dermatan sulfate and heparan
  sulfate affected

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Sphingolipidosis

• TAY-SACHS-hexoamidase a
• Increased gangliosides
• Mental retardation
• Blindness
• Cherry Red Macula
• Muscle weakness
• Seizures
• Fatal
• AUTOSOMAL RECESSIVE

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Sphingolipidosis

• GM-1 Gangliosidosis
• Mental Retardation
• Liver enlargement
• Skeletal deformities
• Accumulation of gangliosides and mps
• Fatal
• AUTOSOMAL RECESSIVE

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Sphingolipidosis

• Sandhoffs Disease
• Same symptoms as Tay-Sachs but more progressive
• AUTOSOMAL RECESSIVE

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Sphingolipidosis

• GAUCHERS- q11-22
• Increases Glucocerebrosides
• Liver and spleen enlargement
• Osteoporosis
• Mental Retardation
• Frequently Fatal
• AUTOSOMAL RECESSIVE

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Sphingolipidosis

• Fabrys Disease (alpha galactosidase)
• Increased Globulosides
• Reddish-purple skin rash
• KIDNEY and Heart
• Pain in Lower extremities
• X-LINKED RECESSIVE

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Sphingolipidosis

• Neimann-Pick Disease
• Increased Sphingomyelin
• Enlarged liver and spleen
• Mental Retardation
• Fatal Early in Life
• Autosomal Recessive

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Sphingolipidosis

• Metachromic Leukodystrophy
• Increased sulfatides
• Mental Retardation
• Demyelination
• Progressive paralysis and dementia
• Nerves stain Yellow-Brown
• Fatal in First Decade
• Autosomal Recessive

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Sphingolipidosis

• FARBERS DISEASE
• (ceraminidase)
• Painful and progressively deformed joints
• Sub Q nodules
• Tissue shows Granuloma
• Fatal early in life
• Autosomal Recessive

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MCAD

• Medium chain Acyl CoA dehydrogenase deficiency.
• Child can get comatose, with brief generalized
  seizures. Intravenous administration of Glucose
  helps the situation.
• NORTHERN EUROPEAN
• Autosomal Recessive

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HNPCC

• Hereditary non-polyposis colerectal cancer is
  Autosomal Dominant
• Often happens before the age of 50 years
• 90 are a mismatch in repair of mutations during
  G2 phase of cell cycle
• Female relative are at risk for endometrial
  carcinomas

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ESSENTIAL AMINO ACIDS

• This Lying Mr. Liu Pong Is Trying Very
  Hard."This-
  ThreonineLying- LysineMr-
  MethionineLiu-
  LeucinePong-
  PhenylalanineIs-
  IsoleucineTrying-
  TryptophanVery-
  ValineHard- Histidine in
  infants

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CARBONIC ANHYDRASE LOCATIONS

• P PECKERS"P-PancreasP-Parietal cells (gastric
  mucosa)E-ErythrocyteC-CNSK-Kidney
  (PCT)E-EyesR-Respiratory (lungs)S-Saliva

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IRON VALANCES

• Iron valenceFerroUS - Fe2 - just the 2 of US
• FerRic - Fe3 - Rich in positive charge

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BASIC AMINO ACIDS

• Basic amino acids - positively charged at pH
  6.0"H-A-L's Base voice earned him much Argent
  Arg, a Positive event."H-
  HistidineA- ArginineL- Lysine

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Negativily Charged

• Acidic amino acids - negatively charged at pH
  6.0"G-A-gging on Acid is a Negative
  experience."G-Glutamic acidA-Aspartic acid

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Embden-Meyerhoff Pathway

• BLOOD CELL ENZYMES

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Hexokinase Deficiency (HK)

• HK is a major determination of glucose
  consumption and of the formation of a first
  enzyme in the glycolytic pathway.
• Shown most with reticulocytes since enzyme is
  highly inactive after RBCs mature

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Phosphofructokinase Deficiency
(PFK)

• PFK is tetrameric enzyme that has effects in
• M(muscle)
• F (fibroblast, platelets)
• L (granulocytes)

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Pyruvate Kinase (PK)Deficency

• The most common enzyme deficiency in
  Embden-myerhoff

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Enzymes of HMP shunt
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Glucose-6-Phosphate dehydrogenase G6-PD

• G6PD is an inborn error of erythrocyte metabolism
  affecting most geographic areas around the world.
• Affected by some race effects
• It involves the HMP shunt
• bandXq28

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Pyruvate Dehydrogenase

• This is found in Chronic alcoholics, present with
  a lateral gaze and difficulty walking.
• May be Weirnicke encephalopathy
• It is caused by Thiamine deficiency in which TPP
  is needed for pyruvate dehydrogenase

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Vitamins
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Non B complex

• Ascorbic Acid-
• Well documented as a coenzyme for hydrolylization
  of lysyl and propl residues in collagen
• Benefit as an antioxidant- except for a presence
  of high Iron
• Deficiency-SCURVY

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Fat Soluble Vitamins

• Vitamin A
• Vitamin D
• Vitamin K
• Vitamin E

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Vitamin A (retinol)

• Vit A is a collective term for several
  biologically related active molecules
• Retinol-is a primary alcohol with an unsaturated
  side chain-Found in animal tissue as long fatty
  acids
• Retinal-an aldehyde that can readily be converted
• B-Carotene-activity 1/6th of retinol
• Functions-visual cycle-growth-reproduction-differe
  ntiation of cells
• Toxicity is well noted especially in pregnant
  women.
• Transported as Chylomicrons

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Vitamin D (1, 25 Dihydoxycholeecalciferol)

• D2 and D3 are bioactive-employing cyto p450. It
  is tightly regulated by plasma phosphate and
  calcium ions.
• Overall function is to increase uptake of calcium
  by intestines
• It stimulate calcium and phosphate from bone to
  maintain plasma levels
• Diseases-Rickets in adult
• Osteomalacia in adults
• Found in milk supplemented--sunlight
• NOTEVIT D is the MOST TOXIC OF ALL VITAMINS

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Vitamin K Menaquinone

• Vit K is required for Hepatic synthesis of
  Clotting Factors II, VII, IX, X (1972)
• Found in cabbage, cauliflower and spinach,
  eggyolk, and liver
• Deficiency leads to
• hypo-prothrombinism
• Newborns require one dose because inability to
  synthesize

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Vitamin E alpha-tocopherol

• Found in liver and eggs and fish oil
• Infants may have deficiency to vitamin E,
  therefore erthrocytes mat may have obscure cell
  membrane
• Vitamin E in supplements of 400 IU may reduced
  heart disease by 40 by decreasing LDL

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Water Soluble Vitamins
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Thiamine(B-1) energy releasing

• Thiamine pyrophosphate is a bioactive coenzyme in
  the oxidative-decarboxylation of
  alpha-ketoacidstransketolase
• This decrease the function of pyruvate
  dehydrogenase
• Clinically
• Beri-Beri-Infants-Tachycardia, vomiting, Adults
  dryskin, irritability and progressive paralysis
• Wernicke-Korsakoff Syndrome-ALCOHOLICS

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Riboflavin (B-2) energy releasing

• Flavins (FMN) and (FAD) are formed by the
  transfer of ATP, they are in an
  oxidation-reduction reaction
• Found in Milk, eggs, liver and green vegetables
• The vitamin is destroyed by ultraviolet light
• Deficiency-cheliosis,glossitis

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Niacin (B-3)

• Niacin or nicotinic acid is a pyridine derivative
• Serves as a coenzyme for (NAD and NADP)
• Found in Whole Grains and Milk
• Def Pellegra (dementia, diarrhea, dermititis)
• USED in Treatment of Hyperlipidemia-decreasing
  triaclyglycerol synthesis and Decreasing LDL and
  VLDL-
• Specifically TYPE II b Hyperlipoprotienemia

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Biotin

• Coenzyme in carboxylation reactions
• Very rare deficiency
• Some people with an addition to RAW EGGS, could
  in fact have an effect because the glycoprotein
  AVIDIN does bind to it tightly.
• gt than 20 raw eggs a day

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Panthothenic Acid

• CoA-functions in the transfer of the Acyl Group
• Serves as a component of FATTY ACID SYNTHASE
• Eggs, Liver and yeast are common sources..FDA has
  no established criteria

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FOLIC ACID-hematopoetic

• Most Common Vitamin Deficiency
• Bio active form is (THF) which is produced by a
  two step reduction of folate by Dihydrofolate
  reductase
• Sulfonamides and Methotrexate used this chain in
  their action
• Found in Green Vegetables, lima beans and whole
  grain cereals (or Bacteria)
• DEPENDENCY-First week of Pregnancy
• DX-Megaloblastic Anemia
• Dx-Neural Tube Defects

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Colbalmin (B-12)corrin ring hematopoietic

• When fatty acids accumulate into cell membranes
  B12 deficiency may show neurological
  manifestations
• B12 deficiency also happens in total or partial
  gastrectomy
• PERNICIOUS ANEMIA-is probably due to an
  Auto-immune destruction of Gastric Parietal Cells
  and responsible for the synthesis of a
  glycol-protein called Intrinsic Factor (IF)
• Lack of (IF) prevents abscoption of B-12
  therefore Pernicious Anemia

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Pyridoxine

• B6 is an enzyme that functions in many reactions
• Transamination
• Deamination
• Decarboxylation
• Condensation
• Requirements increased by a large amountt of
  proteins
• Isoniazid, a TB drug can decrease B6