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The use of enzymes in the diagnosis of disease is one of the important benefits derived from the intensive research in biochemistry since the 1940's

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Title: The use of enzymes in the diagnosis of disease is one of the important benefits derived from the intensive research in biochemistry since the 1940's


1
Introduction The use of enzymes in the
diagnosis of disease is one of the important
benefits derived from the intensive research in
biochemistry since the 1940's Enzymes have
provided the basis for the field of clinical
chemistry It is, however, only within the recent
past few decades that interest in diagnostic
enzymology has multiplied Many methods currently
on record in the literature are not in wide use,
and there are still large areas of medical
research in which the diagnostic potential of
enzyme reactions has not been explored at all
2
Early Enzyme Discoveries Some of the earliest
studies were performed in 1835 by the Swedish
chemist Jon Jakob Berzelius who termed their
chemical action catalytic It was not until 1926,
however, that the first enzyme was obtained in
pure form, a feat accomplished by James B. Sumner
of Cornell University Sumner was able to isolate
and crystallize the enzyme urease from the jack
bean. His work was to earn him the 1947 Nobel
Prize John H. Northrop and Wendell M. Stanley
of the Rockefeller Institute for Medical Research
shared the 1947 Nobel Prize with Sumner. They
discovered a complex procedure for isolating
pepsin.
3
Enzymes and Life Processes The living cell is
the site of tremendous biochemical activity
called metabolism This is the process of
chemical and physical change which goes on
continually in the living organism Build-up of
new tissue, replacement of old tissue, conversion
of food to energy, disposal of waste materials,
reproduction - all the activities that we
characterize as "life." The greatest majority of
these biochemical reactions do not take place
spontaneously The phenomenon of catalysis makes
possible biochemical reactions necessary for all
life processes
4
Catalysis Catalysis is defined as the
acceleration of a chemical reaction by some
substance which itself undergoes no permanent
chemical change The catalysts of biochemical
reactions are enzymes and are responsible for
bringing about almost all of the chemical
reactions in living organisms Without enzymes,
these reactions take place at a rate far too slow
for the pace of metabolism
5
Chemical Nature of Enzymes.                     
                                             
       
6
Many enzymes require the presence of other
compounds - cofactors - before their catalytic
activity can be exerted. This entire active
complex is referred to as the holoenzyme i.e.,
apoenzyme (protein portion) plus the cofactor
(coenzyme, prosthetic group or metal-ion-activator
) is called the holoenzyme.                     
                            Apoenzyme
Cofactor Holoenzyme 1. - A coenzyme - a
non-protein organic substance which is
dialyzable, thermostable and loosely attached to
the protein part. 2. - A prosthetic group - an
organic substance which is dialyzable and
thermostable which is firmly attached to the
protein or apoenzyme portion. 3. - A
metal-ion-activator - these include K, Fe,
Fe, Zn, Mg, Ca
7
Specificity of Enzymes One of the properties of
enzymes that makes them so important as
diagnostic and research tools is the specificity
they exhibit relative to the reactions they
catalyze Other enzymes will be specific for a
particular type of chemical bond or functional
group In general, there are four distinct types
of specificity A- Absolute specificity - the
enzyme will catalyze only one reaction. B-
Group specificity - the enzyme will act only on
molecules that have specific functional groups,
such as amino, phosphate and methyl groups. C-
Linkage specificity - the enzyme will act on a
particular type of chemical bond regardless of
the rest of the molecular structure. D-
Stereochemical specificity - the enzyme will act
on a particular steric or optical isomer.
8
Enzymes can be classified by the kind of chemical
reaction catalyzed 1- Addition or removal of
water A-Hydrolases - these include esterases,
carbohydrases, nucleases, deaminases, amidases,
and proteases B-Hydrases such as fumarase,
enolase, aconitase and carbonic anhydrase 2-
Transfer of electrons A-Oxidases B-Dehydrogenas
es 3- Transfer of a radical A-Transglycosidases
- of monosaccharides B-Transphosphorylases and
phosphomutases - of a phosphate
group C-Transaminases - of amino
group B-Transmethylases - of a methyl
group C-Transacetylases - of an acetyl group 4-
Splitting or forming a C-C bond
A-Desmolases 5- Changing geometry or structure
of a molecule A-Isomerases 6- Joining two
molecules through hydrolysis of pyrophosphate
bond in ATP or other tri-phosphate A- Ligases
9
Enzyme Kinetics Energy Levels              
                                                  
The enzyme is thought to reduce the "path" of
the reaction. This shortened path would require
less energy for each molecule of substrate
converted to product. Given a total amount of
available energy, more molecules of substrate
would be converted when the enzyme is present
(the shortened "path") than when it is absent.
Hence, the reaction is said to go faster in a
given period of time.
10
Enzyme Kinetics Basic Enzyme Reactions The
basic enzymatic reaction can be represented as
follows                                         
      where E represents the enzyme
catalyzing the reaction, S the substrate, the
substance being changed, and P the product of the
reaction.
                                        If
this reaction is combined with the original
reaction above equation the following results
                                                  
          
11
Chemical Equilibrium The study of a large number
of chemical reactions reveals that most do not go
to true completion. This is likewise true of
enzymatically-catalyzed reactions. This is due to
the reversibility of most reactions. In general
where K1 is the forward reaction rate
constant and K-1 is the rate constant for the
reverse reaction. Combining the two reactions
gives                                         
Applying this general relationship to enzymatic
reactions allows the equation
                                                  
Equilbrium, a steady state condition, is
reached when the forward reaction rates equal the
backward rates. This is the basic equation upon
which most enzyme activity studies are based.
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Sugars Prefer To Be Cyclic
15
Carbohydrates Are Chiral Molecules
  • Typically but not always
  • L amino acids
  • D - sugars

D
Hence, these molecules have a measurable optical
rotation, which depends upon both the monomer
residues and their conformation
L Glyceraldehyde
16
Fisher Formulas
Next to last carbon determines D or L
New carbon is added as C1
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Hormones
30
A hormone Is a chemical messenger that carries a
signal from one cell (or group of cells) to
another via the blood. hormone "A chemical
secreted by cells in one part of the body that is
transported in the bloodstream to other parts of
the body, where it affects particular target
cells." - example hypothalamus,
pituitary All multicellular organisms produce
hormones Endocrine hormone molecules are
secreted (released) directly into the
bloodstream, while exocrine hormones (or
ectohormones) are secreted directly into a duct,
and from the duct they either flow into the
bloodstream or they flow from cell to cell by
diffusion in a process known as paracrine
signalling.
31
Hierarchical nature of hormonal control Hormonal
regulation of some physiological activities
involves a hierarchy of cell types acting on each
other either to stimulate or to modulate the
release and action of a particular hormone. The
secretion of hormones from successive levels of
endocrine cells is stimulated by chemical signals
originating from cells higher up the hierarchical
system. The master coordinator of hormonal
activity in mammals is the hypothalamus, which
acts on input that it receives from the central
nervous system Other hormone secretion occurs in
response to local conditions, such as the rate of
secretion of parathyroid hormone by the
parathyroid cells in response to fluctuations of
ionized calcium levels in extracellular fluid.
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Function of hormones ?? HOMEOSTASIS ??
Reproduction ?? Growth and development ??
Maintenance of internal environment ??
Production, utilization and storage of energy
34
Chemical nature of hormones ?? Can be divided
into 3 Groups ?? Amino acid derivatives ??
Peptide hormones ?? Lipid derivatives
35
Amino acid derivatives ?? Derivatives of
tyrosine ?? Catecholamines (epinephrine,dopamine)
?? Thyroid hormones (dipeptides) ?? Tryptophan
derivative ?? Melatonin
36
Peptide hormones ?? Glycoproteins from anterior
pituitary ?? thyroid-stimulating hormone
(TSH) ?? luteinizing hormone (LH) ??
follicle-stimulating hormone (FSH) ?? Peptides
and small proteins ?? Digestive tract
hormones ?? Pituitary hormones ?? Pancreatic
hormones
37
classes of lipid derived hormones ?? Steroid
hormones ?? derived from cholesterol ?? 2
groups ?? with the intact steroid ring (adrenal
and gonadal steroids) ?? with the steroid ring
cleaved (metabolites of vit D) ??
Eicosanoids ?? derived from arachidonic acid
38
Hormone receptors ?? Molecules within or on the
surface of target cells that bind hormones with
high affinity and specificity and thereby
initiate and mediate biological responses ??
Hormones will only produce the response in cells
that express the receptors for this particular
hormone (target cells) ?? ONLY target cells
respond to hormone ?? Cells that do not have
receptors for the hormone ignore the hormone
39
Steroid hormones     The steroid hormones are
all derived from cholesterol. Moreover, with the
exception of vitamin D, they all contain the same
cyclopentanophenanthrene ring and atomic
numbering system as cholesterol. The important
mammalian steroid hormones are shown below along
with the structure of the precursor, pregneolone.
Retinoic acid and vitamin D are not derived from
pregnenolone, but from vitamin A and cholesterol
respectively.
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Vitamins
43
History ?? Purified diets of carbohydrate,
protein, fat, minerals and water were not capable
of normal growth ?? Accessory growth
factors ?? Casimir Funk, a Polish biochemist,
isolated an antiberberi substance from rice
polishings ?? Named it vitamine, an amine, vital
for life
Vitamins ?? Essential organic compounds required
in very small amounts (micronutrients) involved
in fundamental functions of the body ??
Unrelated chemically
44
Vitamins ?? Not metabolic fuels (like glucose or
fatty acids) or structural nutrients (like amino
acids) ?? Regulators (catalysts) of reactions,
some of which are involved in energy
Metabolism ?? Organic molecules in food ??
Required in small amounts ?? Classified based on
solubility ?? Fat soluble ?? Water soluble
45
Classification of vitamins
Water-soluble Vitamins
Fat-soluble Vitamins
46
Vitamins ?? All vitamins are metabolically
essential but not all required in the diet ??
Most mammals can synthesize vitamin C not humans
and primates ?? No mammal can synthesize B
vitamins but rumen bacteria do
47
The Basics of Water-Soluble Vitamins ?? Dissolve
in water ?? B vitamins vitamin C ?? Absorbed
mostly in small intestine stomach ??
Bioavailability ?? Nutritional status, other
nutrients substances in food, medications, age,
illness ?? Circulated to liver in blood ?? Not
stored in large quantities
48
The Basics of Water-Soluble Vitamins
49
Naming the Vitamins ?? First named vitamin A or
B ?? B-complex vitamins ?? Given common names
also ?? Thiamin ?? Riboflavin ?? Niacin ??
Chemical names ?? Ascorbic acid
50
Thiamin (Vitamin B1) ?? Contains thiol amine
group (-SH) and (NH3) ?? Thiamin pyrophosphate
(TPP) or thiamin diphosphate ?? Thiamin
triphosphate
Functions of Thiamin ?? ATP production ??
Synthesis of DNA RNA ?? Noncoenzyme roles
51
Coenzyme Functions of Riboflavin (B2) ?? Energy
metabolism ?? Redox reactions ?? Formation of
ATP, water, carbon dioxide ?? ß-oxidation ??
Converts vitamin A folate to active forms,
tryptophan to niacin ?? Forms vitamin B6 K
Riboflavin Deficiency ?? Ariboflavinosis ??
Weakness, cheilosis, stomatitis, glossitis,
anemia, confusion ?? Alcoholics ?? Diseases
that interfere w/ riboflavinutilization
52
Regulation of Vitamin B12 in the Body ?? Must be
cleaved before absorption ?? Bound to R protein
intrinsic factor ?? Once absorbed, binds to
transcobalamin ?? Circulates to liver via
blood ?? Stored in liver Functions of Vitamin
B12 Coenzyme that catalyzes Production of
succinyl CoA ?? Uses amino acids fatty acids
for ATP production ?? Conversion of homocysteine
to methionine ?? Allows use of folate
53
Regulation of Vitamin C in the Body ??
Absorption in small intestine via active
transport ?? Uses glucose transport protein ??
High intakes ?? Absorbed by simple diffusion in
stomach small intestine ?? Circulates to liver
via blood ?? Excess excreted in urine
Functions of Vitamin C ?? Antioxidant ?? Accepts
donates electrons ?? Involved in a variety of
redox reactions
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