Medical Biochemistry Robert F. Waters, PhD

Medical BiochemistryMedical BiochemistryRobert F. Waters, PhDRobert F. Waters, PhD

Overview

Medical Biochemistry Medical Biochemistry OverviewOverview

Course Overview– Carbohydrate Metabolism

Sugars, Starches, Digestion, Absorption, Energy

– Lipid Metabolism Digestion, Absorption, Transport, Mobilization

– Amino Acids and Proteins Production, Breakdown, Conversion

– Nucleic Acids, DNA and RNA Production, Breakdown

Medical Genetics

MetabolismMetabolism

AnabolismCatabolismConversion into derivatives

– e.g histidine to histamine– Tyrosine to thyroxines– Tyrosine to melanin– Choline to acetylcholine

Mycotoxins (Silent Killer)Mycotoxins (Silent Killer)

Example is aflatoxin (B1,B2,G1,G2)– Converted to M1 in liver and P1 in kidney (urine)– Carcinogenic– Negatively affects immune system

Where do they come from?– Molds growing on plant material produce toxins

Other toxins– Fumonison(horses) [10-15-ppm], vomitoxin, bovarison

Low Level RadiationLow Level Radiation

Proposed by Dr. Sternglas– Sr90 is a - emmitter– Mimics calcium in bone marrow– Negative impact on immune system– Low birth weights– High cancer rates– MS (Multiple Sclerosis)– Neurological Disorders

Chemistry ReviewChemistry Review

Inorganic ChemistryOrganic ChemistryBiochemistry

Cations and Anions—Cations and Anions—Mono-,Di, and TrivalentMono-,Di, and Trivalent

Na+ Fe++,Fe+++

Cu+, Cu++HCO3

- NO2-

K+ NH4+ PO4

--- HClO-

H+ Cl-, F- SO4--

Mg++,Mn++ I- [OH]-

Ca++ CO3-- NO3

-

Inorganic ChemistryInorganic Chemistry

Water– Poiseulles’ Law

Non-compressible Friction Diameter associated with area Pressure Viscosity (n) Length (l)

nl

pr

nl

rprQ

88

))()(( 422

PinPoutp

2r

Poiseulles’ Law ContinuedPoiseulles’ Law Continued

Linear decrease in size decreases area exponentially

Arterial Plaque Formation– Example of Arteriosclerosis

If r=10 r4=10000 If r=9 (10%less) r4=6561 (35% less) If r=5 (50%less) r4=625 (93.75% less!)

Concentration of WaterConcentration of Water

1 liter=1000 gm18gm/mole (Gram Equivalent)

– O = 16– 2 H = 2

Number of Moles per liter

Number of Molecules per liter

lmmolegm

/5.55/18

1000

]10*02.6[*5.55 23

Example of Number of Example of Number of Molecules of Oxygen in a Molecules of Oxygen in a BreathBreathExample to be completed by student

– Assume 1 liter breath– Diatomic Oxygen

pHpH Hydrogen Ion Concentration Dissociation of Water

P= - logarithm

7 + 7 = 14 Acidity vs. Alkalinity pH in living systems

14101]][[ OHHkw

pkwpOHpH

Atomic StructureAtomic Structure

Bohr Concept– Shells, sub-shells, orbitals– Quantum structure vs. Sun and Planet

revolution– Electron spin on orbitals– Example of Chlorophyll– Pauli Exclusion Principle

Pauli Exclusion PrinciplePauli Exclusion Principle

Example of CarbonCarbon

– 2 electrons in first shell (sub-shell) (1s)– Second shell has two sub-shells 2s and 2p– 2s has one orbital and 2p has 3 orbitals– Initially 2s has two electrons and two of the

three 2p orbitals have 1 electron– 1 2s electron is promoted to 3rd 2p orbital

Pauli Exclusion Principle Pauli Exclusion Principle Cont.Cont.

Now forms sp3 Configuration2 electrons in 1s and 1 electron in 2s orbital

and each of the three 2p orbitalsCarbon now has 4 electrons to share giving

it a valence of 4Example of Methane with angle between

hydrogen bonds being 109.5o

Chemical BondsChemical Bonds

IonicCrystalCovalentHydrogen (Weak)Van der Waals Forces

ReactionsReactions

Exothermic

Endothermic

OHCOOCH 2224 22

Elementary Composition of Elementary Composition of Body-Dry Weight BasisBody-Dry Weight Basis

Carbon=50% P=2.5% Magnesium=0.1

Oxygen=20% K=1.0% Iron=0.01%

Hydrogen=10% Sulfur=0.8% Mn=0.001%

Nitrogen=8.5% Sodium=0.4% Iodine=0.00005

Calcium=4.0% Chlorine=0.4% Many Others

Organic ChemistryOrganic Chemistry

CHO PrimarilyEthane, Ethylene,AcetyleneBenzeneMethane

IsomersIsomers Structural Isomers

– Ethanol and Dimethyl Ether Geometric Isomers

– Trans-2-butene, Cis-2-butene Stereochemistry and Stereoisomerism

– Polarimeter– D vs. L– d-Lactate, l-Lactate (dextrorotary(+), levorotary(-))– Chirality (rotational aspect of molecule)– Enantiomeres (Isomers that are mirror images of each other)

Same physical properties except for rotation of light---maybe different biochemical properties!

– Racemic mixture-mixture in solution of enantiomeres– Orientation around a chiral center based on atomic number where highest atomic

number has highest priority. Highest to lowest from left to right is R and the opposite direction is S (Lt:rectus-right & sinister-left)

Major GroupsMajor Groups

R-OH Hydroxyl R-NHx Amino R-COOH Carboxyl R-CHO Carbonyl (Aldehyde) R-CO-R Ketone R-CH3 Methyl

R-PO4 Phosphate

R-SH Sulfhydryl

Functional Aspect of GroupsFunctional Aspect of Groups

Alkyl CH3-(CH2)n-

Alkene -C=C- Aromatic Alcohol R-OH Amines R-NH2

Sulfur Derivatives– R-SH Sulfhydryl (Thiol)– R-S-S-H Disulfide

Functional Aspect of Groups-Cont.Functional Aspect of Groups-Cont.

Carbonyl Groups (R-CHO)– Aldehyde R-CHO– Ketone R-CO-R– Carboxylic Acid R-COOH– Ester R-COO-R’

– Amide R-CO-NH2

Multifunctional GroupsMultifunctional Groups

Hydroxy Acid R-COH-COOHKeto Acid R-CO-COOHDicarboxylate HOOC-R-COOHPhosphates

– PO4= Pi

– Pyroposphate PPi

– Triphosphate R-P-P-P

Consistancy of Blood Plasma Consistancy of Blood Plasma (Age 40)(Age 40)

Na=136-149 meq/L

Albumin=3.5-5.0 g/dl

Cholesterol (total)=150-260mg/dl

Phenylalanine=0.8-1.8mg/dl

Chloride=118-132 meq/L

Transferrin=220-400 mg/dl

Triglyceride=56-298mg/dl

Iron=50-170ug/dl

Bicarbonate= 18-23 meq/L

Ceruloplasmin=18-45mg/dl

Calcium=8.4-10.2mg/dl

Vitamin A =30-65ug/dl

Protein=6.4-8.3 g/dl

Glucose(fasting)=70-105mg/dl

Glutamine=6-16mg/dl

Vitamin D =14-42 ng/dl

(25-OH)

Animal Cell StructureAnimal Cell Structure Plasma Membrane Nucleus Nucleolus Nuclear Membrane RER SER MTOC (Centrioles) Mitochondria Cytosol Cytoplasm? Golgi Body Vesicles Lysosomes Microsomes

Nucleus

Plant Cell StructurePlant Cell Structure

ChloroplastsCell Wall Starch GranulesEtc.

Plant and Animal Plant and Animal BiochemistryBiochemistry

Plant BiochemistryAnimal Biochemistry

– Animal Science vs. Human Nutrition

StarchesStarches

AmyloseAmylopectinGlycogen

SugarsSugars

Sugars– Monosaccharides

Glucose, fructose, galactose, mannose

– Disaccharides Lactose, sucrose, maltose

– Polysaccharides Glycogen, starch, cellulose

Triose Pentose Hexose

GlycogenGlycogen

Branched Chain Polysaccharide– Approx. every 8 glucose a branch (alpha 1,6)– Bond between glucose (alpha 1,4)

Efficient energy storageMainly liver (also other tissues)

CelluloseCellulose

Relatively Linear – Beta 1,4

Other SugarsOther Sugars

ChitinArabinogalactanOlimeric Proanthocyanidins (OPCs)

DigestionDigestion Breakdown of Starch

-1,4 -Amylase

– Maltotriose OOO– Maltose OO– Dextrins – fragments of branched and unbranched starches– Isomaltose Two Glucose -1,6– Sucrose– Lactose (Infantile)– Trehalase-Some people lack enzyme and acts like mushroom

poisoning. Trehalose in foods like mushrooms

EnzymesEnzymes

IsomaltaseLactase (-galactosidase)SucraseMaltase

Insulin/Glucagon and Insulin/Glucagon and Glucose-Glucose Glucose-Glucose HomeostasisHomeostasisMain Metabolic Fuels are Glucose and

Fatty AcidsLong Chain Fatty Acids are Ideal Fuel

Storage 9 kcal/g vs. 4 kcal/g for carbs and proteins

Amino Acids can be fuel during fasting, illness, or injury

If you ate a 3oz. Donut in the If you ate a 3oz. Donut in the morning & assume 100% morning & assume 100% carbohydrate---carbohydrate---How many calories would you have

ingested? – ~4 Kcal/g– 16 oz/lb– 454 gm/lb– 3oz/16oz x 454gm = 85 gm– 85gm x 4 Kcal/gm = 340 Kcal/donut

If you ate a 3oz. Donut in the If you ate a 3oz. Donut in the morning & assume 100% morning & assume 100% carbohydrate---carbohydrate---What % of your average daily caloric intake

does this represent?– 1800 Kcal / day (1500-2200)– 340Kcal/1800Kcal X 100 = ~20%

If you ate a 3oz. Donut in the If you ate a 3oz. Donut in the morning & assume 100% morning & assume 100% carbohydrate---carbohydrate---What % of the donut’s energy would be

used by the brain?– Brain needs 100-120gm of glucose per day.

(400-480 Kcal/day)– 340Kcal/440Kcal x 100 = ~75%

If you ate a 3oz. Donut in the If you ate a 3oz. Donut in the morning & assume 100% morning & assume 100% carbohydrate---carbohydrate---How long could the brain function on the

energy from one donut?– Brain needs 100-120 gm or ~440Kcal/day– 340Kcal/440Kcal x 24 hrs = 18 hrs

GluconeogenesisGluconeogenesis

Occurs primarily in liverStimulated by epinephrine

Glucose HomeostasisGlucose Homeostasis Hypoglycemic Action-Insulin Hyperglycemic Action-Glucagon, epinephrine,cortisol, Growth

Hormone (GH) Insulin

– Produced by -cells (70% of islet cells)– Glucagon secreted by -cells– Pre-proinsulin, pro-insulin, insulin

C-peptide (-cell Assessment) Insulin-2 chains (-21AAand -30AA) connected by 2 disulfide bonds

– Biphasic Secretion Insulin Receptors and Glucose Receptors TNF- inhibits glucose receptor Type I and Type II Diabetes

Alcoholism and HypoglycemiaAlcoholism and Hypoglycemia

Inhibits Thiamine absorption in gutInhibits Lactate Dehydrogenase (Reverse)Liver Pyruvate levels dropHypoglycemic due to inhibited

gluconeogenesis (anabolic)

Alcohol Consumption Alcohol Consumption Continued;Continued;

Animal cells contain alcohol dehydrogenase (ADH) which oxidizes ethanol to acetaldehyde. Acetaldehyde is oxidized to acetate by acetaldehyde dehydrogenase (AcDH). Acetaldehyde and acetate are toxic leading to the many side effects (the hangover) that are associated with alcohol consumption. The ADH and AcDH catalyzed reactions also leads to the reduction of NAD+ to NADH. The metabolic effects of ethanol intoxication stem from the actions of ADH and AcDH and the resultant cellular imbalance in the NADH/NAD+. The reduction in NAD+ impairs the flux of glucose through glycolysis at the glyceraldehyde-3-phosphate dehydrogenase reaction, thereby limiting energy production. Additionally, there is an increased rate of hepatic lactate production due to the effect of increased NADH on direction of the hepatic lactate dehydrogenase (LDH) reaction. This reverseral of the LDH reaction in hepatocytes diverts pyruvate from gluconeogenesis leading to a reduction in the capacity of the liver to deliver glucose to the blood.