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General Metabolism I

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General Metabolism I Andy Howard Introductory Biochemistry 6 November 2008 What we ll discuss Metabolism Definitions Pathways Control Feedback Phosphorylation ... – PowerPoint PPT presentation

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Title: General Metabolism I


1
General Metabolism I
  • Andy HowardIntroductory Biochemistry
  • 6 November 2008

2
What well discuss
  • Metabolism
  • Definitions
  • Pathways
  • Control
  • Feedback
  • Phosphorylation
  • Thermodynamics
  • Kinetics
  • Cofactors
  • Tightly-bound metal ions as cofactors
  • Activator ions as cofactors
  • Cosubstrates
  • Prosthetic groups

3
Metabolism
  • Almost ready to start the specifics(chapter 18)
  • Define it!Metabolism is the network of chemical
    reactions that occur in biological systems,
    including the ways in which they are controlled.
  • So it covers most of what we do here!

4
Intermediary Metabolism
  • Metabolism involving small molecules
  • Describing it this way is a matter of
    perspectiveDo the small molecules exist to give
    the proteins something to do, or do the proteins
    exist to get the metabolites interconverted?

5
Anabolism and catabolism
  • Anabolism synthesis of complex molecules from
    simpler ones
  • Generally energy-requiring
  • Involved in making small molecules and
    macromolecules
  • Catabolismdegradation of large molecules into
    simpler ones
  • Generally energy-yielding
  • All the sources had to come from somewhere

6
Common metabolic themes
  • Maintenance of internal concentrations of ions,
    metabolites, enzymes
  • Extraction of energy from external sources
  • Pathways specified genetically
  • Organisms cells interact with their environment
  • Constant degradation synthesis of metabolites
    and macromolecules to produce steady state

7
Metabolism and energy
8
Pathway
  • A sequence of reactions such that the product of
    one is the substrate for the next
  • Similar to an organic synthesis scheme(but with
    better yields!)
  • May be
  • Unbranched
  • Branched
  • Circular

9
Why multistep pathways?
  • Limited reaction specificity of enzymes
  • Control of energy input and output
  • Break big inputs into ATP-sized inputs
  • Break energy output into pieces that can be
    readily used elsewhere

10
Regulation
  • Organisms respond to change
  • Fastest small ions move in msec
  • Metabolites 0.1-5 sec
  • Enzymes minutes to days
  • Flow of metabolites is flux
  • steady state is like a leaky bucket
  • Addition of new material replaces the material
    that leaks out the bottom

11
Metabolic flux, illustrated
  • Courtesy Jeremy Zuckers wiki

12
Feedback and Feed-forward
  • Mechanisms by which the concentration of a
    metabolite that is involved in one reaction
    influences the rate of some other reaction in the
    same pathway

13
Feedback realities
  • Control usually exerted at first committed step
    (i.e., the first reaction that is unique to the
    pathway)
  • Controlling element is usually the last element
    in the path

14
Feed-forward
  • Early metabolite activates a reaction farther
    down the pathway
  • Has the potential for instabilities, just as in
    electrical feed-forward
  • Usually modulated by feedback

15
Activation and inactivation by post-translational
modification
  • Most commoncovalent phosphorylation of protein
  • usually S, T, Y, sometimes H
  • Kinases add phosphateProtein-OH ATP
    ?Protein-O-P ADP ATP is source of energy and
    Pi
  • Phosphatases hydrolyze phosphoesterProtein-O-P
    H2O? Protein-OH Pi no external energy source
    required

16
Phosphorylations effects
  • Phosphorylation of an enzyme can either activate
    it or deactivate it
  • Usually catabolic enzymes are activated by
    phosphorylation and anabolic enzymes are
    inactivated
  • Exampleglycogen phosphorylase is activated by
    phosphorylation its a catabolic enzyme

17
Glycogen phosphorylase
  • Reaction extracts 1 glucose unit from
    non-reducing end of glycogen phosphorylates
    it(glycogen)n Pi ?(glycogen)n-1
    glucose-1-P
  • Activated by phosphorylationvia phosphorylase
    kinase
  • Deactivated by dephosphorylation byphosphorylase
    phosphatase

18
Amplification
  • Activation of a single molecule of a protein
    kinase can enable the activation (or
    inactivation) of many molecules per sec of target
    proteins
  • Thus a single activation event at the kinase
    level can trigger many events at the target level

19
Other PTMs (p. 505)
  • Are there other reversible PTMs that regulate
    enzyme activity? Yes
  • Adenylation of Y
  • ADP-ribosylation of R
  • Uridylylation of Y
  • Oxidation of cysteine pairs to cystine

20
Evolution of PathwaysHow have new pathways
evolved?
  • Add a step to an existing pathway
  • Evolve a branch on an existing pathway
  • Backward evolution
  • Duplication of existing pathway to create related
    reactions
  • Reversing an entire pathway

21
Adding a step
E1
E2
E3
E4
E5
Original pathway
  • A ? B ? C ? D ? E ? P
  • When the organism makes lots of E, theres good
    reason to evolve an enzyme E5 to make P from E.
  • This is how asn and gln pathways (from asp glu)
    work

22
Evolving a branch
  • Original pathway D A ?
    B ? C X
  • Fully evolved pathway D
    A ? B ? C X

E1
E2
E3
E3a
E3b
23
Backward evolution
  • Original system has lots of E ? P
  • E gets depleted over time
  • need to make it from D,
  • so we evolve enzyme E4 to do that.
  • Then D gets depleted
  • need to make it from C,
  • so we evolve E3 to do that
  • And so on

24
Duplicated pathways
  • Homologous enzymes catalyze related
    reactionsthis is how trp and his biosynthesis
    enzymes seem to have evolved
  • Variant recruit some enzymes from another
    pathway without duplicating the whole thing
    (example ubiquitination)

25
Reversing a pathway
  • Wed like to think that lots of pathways are
    fully reversible
  • Usually at least one step in any pathway is
    irreversible (?Go lt -15 kJ mol-1)
  • Say C?D is irreversible so E3 only works in the
    forward direction
  • Then D ATP ?C ADP Pi allows us to reverse
    that one step with help
  • The other steps can be in common
  • This is how glycolysis evolved from
    gluconeogenesis

26
Many cofactors are derived from vitamins
  • We justify lumping these two topics together
    because many cofactors are vitamins or are
    metabolites of vitamins.

27
Family tree of cofactors
  • Cofactors, coenzymes, essential ions,
    cosubstrates, prosthetic groups

Cofactors(apoenzyme cofactor ? holoenzyme)
Essential ions
Coenzymes
Activator ions(loosely bound)
Ions inmetalloenzymes
Prosthetic groups(tightly bound)
Cosubstrates(loosely bound)
28
Metal-activated enzymes
  • Absolute requirements for mobile ions
  • Often require K, Ca2, Mg2
  • Example Kinases Mg-ATP complex
  • Metalloenzymes firmly bound metal ions in active
    site
  • Usually divalent or more
  • Sometimes 1e- redox changes in metal

29
Coenzymes
  • Organic moeities that enable enzymes to perform
    their function they supply functionalities not
    available from amino acid side chains
  • Cosubstrates
  • Enter reaction, get altered, leave
  • Repeated recycling within cell or organelle
  • Prosthetic groups
  • Remain bound to enzyme throughout
  • Change during one phase of reaction, eventually
    get restored to starting state

30
Major cosubstrates
  • Facilitate group transfers, mostly small groups
  • Oxidation-reduction participants
  • Cosubstrate Source Function
  • ATP Transfer P,Nucleotide
  • S-adenosylMet Methyl transfer
  • UDP-glucose Glycosyl transfer
  • NAD,NADP Niacin 2-electron redox
  • Coenzyme A Pantothenate Acyl transfer
  • Tetrahydrofolate Folate 1Carbon transfer
  • Ubiquinone Lipid-soluble e- carrier

31
Major prosthetic groups
  • Transfer of larger groups
  • One- or two-electron redox changes
  • Prosth.gp. Source Function
  • FMN, FAD Riboflavin 1e- and 2e- redox transfers
  • TPP Thiamine 2-Carbon transfers with CO
  • PLP Pyridoxine Amino acid group transfers
  • Biotin Biotin Carboxylation, COO- transfer
  • Adenosyl- Cobalamin Intramolec. rearrangements
  • cobalamin
  • MeCobal. Cobalamin Methyl-group transfers
  • Lipoamide Transfer from TPP
  • Retinal Vitamin A Vision
  • Vitamin K Vitamin K Carboxylation of glu residues

32
Adenosine triphosphate
  • Synthesizable in liver (chapter 18)
  • Building block for RNA
  • Participates in phosphoryl-group transfer in
    kinases
  • Source of other coenzymes

33
S-adenosylmethionine
  • Made from methionine and adenosine
  • Sulfonium group is highly reactive can donate
    methyl groups

Reaction diagram courtesy of Eric Neeno-Eckwall,
Hamline University
34
UDP-glucose
  • Most common donor of glucose
  • Formed viaGlucose-1P UTP?UDP-glucose PPi
  • Reaction driven to right by PPi hydrolysis

Structure courtesy of UIC Pharmacy Program
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