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INTRODUCTION)TO)METABOLISM

Prepared'by:'Robert'Paul'S.'Lim,'RPh
UNIT%EXPECTED%OUTCOMES
At the end of the lecture, the student must be able to:
1. Define and use correctly the terms intermediary or
primary metabolism, catabolism, anabolism,
pathway, feedback, committed step, ATP,
phosphoanhydride, phosphoester, CoA, thioester,
pantothenic acid, nicotinamide, niacin, NADH,
NADPH, pellagra, Flavin, FADH2, FMNH2,
riboflavin, and flavoprotein.
UNIT%EXPECTED%OUTCOMES
At the end of the lecture, the student must be able to:
2. explain the main stages in catabolism.

3. summarize a diagram the main pathways for


digestion of foodstuff.
4. describe the concept of feedback, as applied to
metabolism.
5. identify important common features of metabolic
regulation involving key steps and end products.
UNIT%EXPECTED%OUTCOMES
At the end of the lecture, the student must be able to:
6. Recognize the structures of CoA, NAD, NADH, FAD,
and FADH2.
7. Identify functionally important chemical groups on
CoA, NADH, FAD, and FADH2.
8. write biochemical reactions following the
conventions of IUMB.
Overview'
• Metabolism is the entire network of chemical reactions
carried out by living cells.

• Metabolites are the small molecules that are intermediates


in the degradation or biosynthesis of biopolymers.

• Intermediary or primary metabolism is the collection of


reactions responsible for the generation of energy in the
cell, the use of this energy, and simple organic precursor
molecules to make more complicated molecules for the cell.
Two$parts$of$Metabolism
1. Anabolism or Biosynthesis
• those responsible for the synthesis of all
compounds needed for cell maintenance,
growth, and reproduction.
2. Catabolism or Degradation
• which nutrients and cell constituents are
broken down to salvage their components
and/or to make energy available.
5"COMMON"THEMES"IN"METABOLISM
1. Organisms or cells maintain specific internal
concentrations of inorganic ions,
metabolites, and enzymes.
2. Organisms extract energy from external
sources to drive energyHconsuming
reactions.
3. The metabolic pathways in each organism
are specified by the genes it contains in its
genome.
5"COMMON"THEMES"IN"METABOLISM
4. Organisms and cells interact with their environment.
5. The cells of organisms are not static assemblies of
molecules.
• Many cell components are continually synthesized
and degraded, that is, they undergo turnover, even
though their concentrations may remain virtually
constant.
• The concentrations of other compounds change in
response to changes in external or internal
conditions.
METABOLIC*PATHWAYS
A.#PATHWAYS#ARE#SEQUENCES#OF#
REACTIONS
Metabolic*Pathway
• is the biological equivalent of a synthesis scheme in
organic chemistry.
• is a series of reactions where the product of one
reaction becomes the substrate for the next
reaction.
• may consist of only two steps while others may be
a dozen steps in length.
• is a series of connected enzymatic reactions that
produce specific products. (?)
Forms8of8Metabolic8Pathways
Linear Metabolic Pathway: Cyclic Metabolic Pathway: Citric
Biosynthesis of Serine Acid Cycle
Forms8of8Metabolic8Pathways
Spiral Metabolic Pathway: Branched Metabolic Pathway:
Biosynthesis of Serine Purine Synthesis
Forms&of&Metabolic&Pathways
Vitamins(and(Minerals(Assist(
Metabolic(Reactions
Vitamins(and(Minerals(Assist(
Metabolic(Reactions
B.#METABOLISM#PROCEEDS#BY#
DISCRETE#STEPS
Multistep)Pathways
1. limited reaction specificity of enzymes.
• Each active site catalyzes only a single step of a
pathway.
2. to control energy input and output.
• Energy flow is mediated by energy donors and
acceptors that carry discrete quanta of
• Pathways for the biosynthesis of molecules require
the transfer of energy at multiple points.
• Each energy?requiring reaction corresponds to a
single step in the reaction sequence.
Multistep)Pathways
C.#METABOLIC#PATHWAYS#ARE#
REGULATED
Steady*state

1. Although*many*reactions*are*near*equilibrium,*an*
entire*metabolic*pathway—and*the*cell’s*
metabolism*as*a*whole—never*reaches*
equilibrium. (?)*
2. Metabolic*pathways*proceed,*as*if*trying*to*reach*
equilibrium*but*they*cannot*get*there*because*
new*reactants*keep*arriving*and*products*do*not*
accumulate.*
! Le*Chatelier’s Principle
Mechanisms,of,Regulation
1. ALLOSTERIC,CONTROL

FEEDBACK,REGULATION

FEEDFORWARD,REGULATION
Mechanisms*of*Regulation
2.*COVALENT*MODIFICATION
Mechanisms*of*Regulation
3. GENETIC CONTROL
• Enzyme concentrations, and hence enzyme
activities, may be altered by protein synthesis in
response to metabolic needs.
• The processes of transcribing a gene to
messenger RNA and then translating the RNA to a
polypeptide chain offer numerous points for
regulation.
1. The reactants that originate the process
2. The end products, regardless of being formed in
intermediate reactions or the final reaction
3. The branching points, i.e., steps where the sequence of
reactions may follow different courses.
4. The irreversible reactions.
5. The specific reactions that are catalyzed by enzymes that are
finely regulated and so have the ability to highly accelerate
segments of the metabolism, or not.
• The metabolism is “fed” by A and has K, F, and J as “end
products.”
• An external source of G may also lead to the formation of J
and F, but not K.
• An external source of D can only lead to the formation of F.
However, if ED is not present or not operative, F will not be
formed in any circumstance.
• Likewise, if EB2 is not present or not operative, K, G, H, J, and
I will not be formed even in the presence of high
concentration of B.
• If EB1 and EB2 are never active or inactive at the
same time, F is always formed but not J;
• the reactions’ scheme assures the permanent
formation of F but the selective formation of J when
the control of the reaction course is performed by
alternate states of activity of EB1 and EB2.
MAJOR&PATHWAYS&IN&CELLS
Metabolic*Pathways*Occur*in*
Specific*Cellular*Locations
ENERGY&
RELATIONSHIPS&
BETWEEN&
CATABOLIC&AND&
ANABOLIC&
PATHWAYS
OVERVIEW'OF'ANABOLIC'PATHWAY
OVERVIEW'OF'CATABOLIC'PATHWAY
FOUR%STAGES%OF%CATABOLISM
Stage&1:&Digestion
Stage&1:&Digestion&of&proteins
Stage&1:&Digestion&of&proteins
Stage&1:&Digestion&of&Lipids
Stage&1:&Digestion&of&Lipids
Stage&1:&Digestion&of&Lipids
Stage&2:&Formation&of&Acetyl&
CoA
Stage&3:&The&Citric&Acid&Cycle
STAGE&4:&The&Electron&Transport&Chain&and&
Oxidative&Phosphorylation
MAJOR&TYPES&OF&REACTION
Major&Types&of&Reaction
1. Oxidation7reduction
2. Reactions that make or break carbon–
carbon bonds;
3. Internal rearrangements, isomerizations,
and eliminations;
4. Group transfers;
5. Free radical reactions
OXIDATION(REDUCTION
• The carbon atoms in biological molecules can
assume different oxidation states depending on
the atoms to which they are bonded.
• a carbon atom bonded to less electronegative
hydrogen atoms is least oxidized.
• a carbon atom bonded to highly electronegative
oxygen atoms is most oxidized.
OXIDATION(REDUCTION
OXIDATION(REDUCTION
Reactions*that*make*or*break*
carbon–carbon*bonds
Reactions*that*make*or*break*
carbon–carbon*bonds
Reactions*that*make*or*break*
carbon–carbon*bonds
Reactions'that'make'or'break'
carbon–carbon'bonds
ALDOLASE REACTION

CITRATE'SYNTASE'
REACTION

ACETOACETATE'
DECARBOXYLASE'
REACTION
Early&Steps&in&Cholesterol&
Biosynthesis
Internal(rearrangements,(Isomerizations,(
and(Eliminations
Internal(rearrangements,(Isomerizations,(
and(Eliminations
Internal(rearrangements,(Isomerizations,(
and(Eliminations
Group$transfers
• The$transfer$of$acyl,$glycosyl,$and$phosphoryl$groups
from$one$nucleophile$to$another$is$common$in$living$
cells.$
• Acyl$group$transfer$generally$involves$the$addition$of$
a$nucleophile$to$the$carbonyl$carbon$of$an$acyl$group$
to$form$a$tetrahedral$intermediate.
Group&transfers:&Acyl&group
Group&transfers:&Glycosyl
Group&transfers:&Phosphoryl&
• play a special role in metabolic pathways.
• General theme in metabolism: the
attachment of a good leaving group to a
metabolic intermediate to “activate” the
intermediate for subsequent reaction.
GroupGtransfers:GPhosphorylG
Better Leaving groups in BetterGLeavingGgroupsGinG
Nucleophilic Substitution: NucleophilicGSubstitution:
• Inorganic orthophosphate • inorganic pyrophosphate
(the ionized form of (P2O74D, abbreviated PPi);
H3PO4 at neutral pH, a • esters and anhydrides of
mixture of H2PO4D and phosphoric acid are
HPO42D) effectively activated for
• commonly abbreviated Pi reaction.
Group&transfers:&Phosphoryl&
Group&transfers:&Phosphoryl
Free,Radical,Reactions

RIBONUCLEOTIDE,REDUCTASE
ATP$AND$ENERGY$PRODUCTION
ADENOSINE(TRIPHOSPHATE
ATPFandFADP
• Hydrolysis of ATP cleaves one phosphate group,
forming ADP and hydrogen phosphate, HPO42–,
often abbreviated as Pi (inorganic phosphate).
This reaction releases 7.3 kcal/mol of energy.
ATP?and?ADP
• The reverse reaction, phosphorylation, adds a
phosphate group to ADP, forming ATP.
• Phosphorylation requires 7.3 kcal/mol of energy.
ATP$and$ADP
CONVENTIONSCINCWRITINGC
REACTIONS
• The principal organic reactants and products are
drawn from left to right with a reaction arrow as
usual, but additional compounds like ATP and ADP
are drawn on a curved arrow.
COENZYMES)IN)METBOLISM
COENZYMES
REDOX:'DEFINITION'OF'TERMS
Oxidizing agent
• oxidant

• gains electrons and is reduced in a chemical


reaction.
• Also known as the electron acceptor.
REDOX:'DEFINITION'OF'TERMS
Reducing agent
• reductant

• loses electrons and is oxidized in a chemical


reaction.
• is known as the electron donor.

• A reducing agent is oxidized, because it loses


electrons in the redox reaction.
COENZYMES:*REDOX
• When a coenzyme gains hydrogen atoms—that is,
H+ and e–—the coenzyme is reduced; thus, the
coenzyme is an oxidizing agent.

• When a coenzyme loses hydrogen atoms—that is,


H+ and e–—the coenzyme is oxidized; thus, the
coenzyme is a reducing agent.
NICOTINAMIDE*ADENINE*
DINUCLEOTIDE
Curved'arrow'convention
SAMPLE&PROBLEM
• Label&the&reaction&as&an&oxidation&or&reduction,&and&
give&the&reagent,&NAD+&or&NADH,&that&would&be&used&
to&carry&it&out
SAMPLE&PROBLEM
• Label&the&reaction&as&an&oxidation&or&reduction,&and&
give&the&reagent,&NAD+&or&NADH,&that&would&be&used&
to&carry&it&out.
• Answer:
FAD$and$FADH2