11/17/2010Motors II; Metabolism I Motors II; General Metabolism I Andy Howard Introductory...
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Transcript of 11/17/2010Motors II; Metabolism I Motors II; General Metabolism I Andy Howard Introductory...
11/17/2010Motors II; Metabolism I
Motors II;General
Metabolism IAndy Howard
Introductory Biochemistry, fall 2010
17 November 2010
11/17/2010Motors II; Metabolism I Page 2 of 40
Metabolism:the core of biochem All of biology 402 will concern itself with the specific pathways of metabolism
Our purpose here is to arm you with the necessary weaponry
… but first, we need to explain the role of Ca2+ in muscle contraction
11/17/2010Motors II; Metabolism I Page 3 of 40
What we’ll discuss
Muscle Calcium Ca2+ receptors Troponin C and I
Smooth muscle Metabolism
Definitions Pathways
Metabolism, continued Control Feedback Flux Phosphorylation
Other PTMs Evolution
11/17/2010Motors II; Metabolism I Page 4 of 40
Muscle Contraction Is Regulated by Ca2+Ca2+ Channels and Pumps
Release of Ca2+ from the SR triggers contraction
Reuptake of Ca2+ into SR relaxes muscle
So how is calcium released in response to nerve impulses?
Answer has come from studies of antagonist molecules that block Ca2+ channel activity
11/17/2010Motors II; Metabolism I Page 5 of 40
Ca2+ triggers contraction Release of Ca2+ through voltage- or Ca2+-sensitive channel activates contraction
Pumps induce relaxation
11/17/2010Motors II; Metabolism I Page 6 of 40
Dihydropyridine ReceptorIn t-tubules of heart and skeletal
muscle Nifedipine and other DHP-like molecules bind to the "DHP receptor" in t-tubules
In heart, DHP receptor is a voltage-gated Ca2+ channel
In skeletal muscle, DHP receptor is apparently a voltage-sensing protein and probably undergoes voltage-dependent conformational changes
11/17/2010Motors II; Metabolism I Page 7 of 40
Ryanodine ReceptorThe "foot structure" in terminal
cisternae of SR Foot structure is a Ca2+ channel of unusual design
Conformation change or Ca2+ -channel activity of DHP receptor apparently gates the ryanodine receptor, opening and closing Ca2+ channels
Many details are yet to be elucidated!
11/17/2010Motors II; Metabolism I Page 8 of 40
Ryanodine Receptor
Courtesy BBRI
QuickTime™ and a decompressor
are needed to see this picture.
11/17/2010Motors II; Metabolism I Page 9 of 40
Muscle Contraction Is Regulated by Ca2+
Tropomyosin and troponins mediate the effects of Ca2+
See Figure 16.24 In absence of Ca2+, TnI binds to actin to keep myosin off
TnI and TnT interact with tropomyosin to keep tropomyosin away from the groove between adjacent actins
But Ca2+ binding changes all this!
11/17/2010Motors II; Metabolism I Page 10 of 40
Ca2+ Turns on Contraction
Binding of Ca2+ to TnC increases binding of TnC to TnI, simultaneously decreasing the interaction of TnI with actin
This allows tropomyosin to slide down into the actin groove, exposing myosin-binding sites on actin and initiating contraction
Since troponin complex interacts only with every 7th actin, the conformational changes must be cooperative
11/17/2010Motors II; Metabolism I Page 11 of 40
Thin & thick filaments Changes that happen when Ca2+ binds to troponin C
Fig. 16.24
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Binding of Ca2+ to Troponin C Four sites for Ca2+ on TnC - I, II, III
and IV Sites I & II are N-terminal; III and IV on C term
Sites III and IV usually have Ca2+ bound Sites I and II are empty in resting state Rise of Ca2+ levels fills sites I and II Conformation change facilitates binding of TnC to TnI
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2 views of troponin C Ribbon Molecular graphic
Fig. 16.25
11/17/2010Motors II; Metabolism I Page 14 of 40
Smooth Muscle ContractionNo troponin complex in smooth
muscle In smooth muscle, Ca2+ activates myosin light chain kinase (MLCK) which phosphorylates LC2, the regulatory light chain of myosin
Ca2+ effect is via calmodulin - a cousin of Troponin C
11/17/2010Motors II; Metabolism I Page 15 of 40
Effect of hormones on smooth muscle Hormones regulate contraction - epinephrine, a smooth muscle relaxer, activates adenylyl cyclase, making cAMP, which activates protein kinase, which phosphorylates MLCK, inactivating MLCK and relaxing muscle
11/17/2010Motors II; Metabolism I Page 16 of 40
Smooth Muscle Effectors
Useful drugs Epinephrine (as Primatene) is an over-the-counter asthma drug, but it acts on heart as well as on lungs - a possible problem!
Albuterol is a more selective smooth muscle relaxer and acts more on lungs than heart
Albuterol is used to prevent premature labor
Oxytocin (pitocin) stimulates contraction of uterine smooth muscle, inducing labor
11/17/2010Motors II; Metabolism I Page 17 of 40
Oxytocin structure P.532
11/17/2010Motors II; Metabolism I Page 18 of 40
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!
11/17/2010Motors II; Metabolism I Page 19 of 40
Intermediary Metabolism
Metabolism involving small molecules
Describing it this way is a matter of perspective:Do the small molecules exist to give the proteins something to do, or do the proteins exist to get the metabolites interconverted?
11/17/2010Motors II; Metabolism I Page 20 of 40
How similar are pathways in various organisms? Enormous degree of similarity in the general metabolic approaches all the way from E.coli to elephants
Glycolysis arose prior to oxygenation of the atmosphere
This is considered strong evidence that all living organisms are derived from a common ancestor
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Anabolism and catabolism Anabolism: synthesis of complex molecules from simpler ones Generally energy-requiring Involved in making small molecules and macromolecules
Catabolism: degradation of large molecules into simpler ones Generally energy-yielding All the sources had to come from somewhere
11/17/2010Motors II; Metabolism I Page 22 of 40
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
11/17/2010Motors II; Metabolism I Page 23 of 40
Metabolism and energy
11/17/2010Motors II; Metabolism I Page 24 of 40
Metabolic classifications
Carbon sources Autotrophs vs. heterotrophs Atmospheric CO2 as a C source vs. otherwise-derived C sources
Energy sources Phototrophs vs. chemotrophs (Sun)light as source of energy vs. reduced organic compounds as a source of energy
11/17/2010Motors II; Metabolism I Page 25 of 40
Fourway divisions (table 17.2)
Energy/Carbon Phototrophs:Energy from light
Chemotrophs:Energy from reduced organic molecules
Autotrophs:Carbon from atmospheric CO2
Photoautotrophs:Green plants, cyanobacteria, …
Chemoautotrophs:Nitrifying bacteria, H, S, Fe bacteria
Heterotrophs:Carbon from other [organic] sources
Photoheterotrophs:Nonsulfur purple bacteria
Chemoheterotrophs:Animals, many microorganisms, . . .
11/17/2010Motors II; Metabolism I Page 26 of 40
Another distinction: the organism and oxygen Aerobes: use O2 as the ultimate electron acceptor in oxidation-reduction reactions
Anaerobes: don’t depend on O2
Obligate: poisoned by O2
Facultative: can switch hit
11/17/2010Motors II; Metabolism I Page 27 of 40
Flow of energy
Sun is ultimate source of energy Photoautotrophs drive synthesis of [reduced] organic compounds from atmospheric CO2 and water
Chemoheterotrophs use those compounds as energy sources & carbon; CO2 returned to atmosphere
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How to anabolism & catabolism interact? Sometimes anabolism & catabolism occur simultaneously.
How do cells avoid futile cycling? Just-in-time metabolism Compartmentalization:
Anabolism often cytosolic Catabolism often mitochondrial
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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
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Catabolism stages
Stage 1: big nutrient macromolecules hydrolyzed into their building blocks
Stage 2: Building blocks degraded into limited set of simpler intermediates, notably acetyl CoA
Stage 3: Simple intermediates are fed to TCA cycle and oxidative phosphorylation
11/17/2010Motors II; Metabolism I Page 31 of 40
Anabolism stages
Short list ofsimple precursors
These are elaboratedin characteristic ways to build monomerse.g.: transamination of -ketoacids to make -amino acids
Those are then polymerized to form proteins, polysaccharides, polynucleotides, etc.
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Some intermediates play two roles Some metabolites play roles in both kinds of pathways
We describe them as amphibolic Just recall that:catabolism is many down to few, anabolism is few up to many
11/17/2010Motors II; Metabolism I Page 33 of 40
Differences between catabolic and anabolic pathways Often they share many reactions, notably the ones that are nearly isoergic (Go ~ 0)
Reactions with Go < -20 kJ mol-1 are not reversible as is
Those must be replaced by (de)coupled reactions so that the oppositely-signed reactions aren’t unfeasible
11/17/2010Motors II; Metabolism I Page 34 of 40
Other differences involve regulation Generally control mechanisms
influence catalysis in both directions
Therefore a controlling influence(e.g. an allosteric effector)will up- or down-regulate both directions
If that’s not what the cell needs, it will need asymmetric pathways or pathways involving different enzymes in the two directions
11/17/2010Motors II; Metabolism I Page 35 of 40
ATP’s role We’ve discussedits significance asan energy currency
It’s one of two energy-rich products of the conversion of light energy into chemical energy in phototrophs
ATP then provides drivers for almost everything else other than redox
11/17/2010Motors II; Metabolism I Page 36 of 40
NAD’s role
NAD acts as asan electronacceptor via nettransfer of hydride ions,H:-, in catabolic reactions
Reduced substrates get oxidized in the process, and their reducing power ends up in NADH
Energy implied by that is used to make ATP (2.5 ATP/NAD) in oxidative phosphorylation
QuickTime™ and a decompressor
are needed to see this picture.
Image courtesy Michigan Tech Biological Sciences
11/17/2010Motors II; Metabolism I Page 37 of 40
NADPH’s role
Involved inanabolic redoxreactions
Reducing power in NADPH NADP used to reduce some organic molecule
Involves hydride transfers again NADPH regenerated in phototrophs via light-dependent reactions that pull electrons from water
11/17/2010Motors II; Metabolism I Page 38 of 40
How do we study pathways?
Inhibitor studies Mutagenesis Isotopic traces (radio- or not) NMR Disruption of cells to examine which reactions take place in which organelle
11/17/2010Motors II; Metabolism I Page 39 of 40
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
11/17/2010Motors II; Metabolism I Page 40 of 40
iClicker quiz question 1
A reaction A+B C+D proceeds from left to right in the cytosol and from right to left in the mitochondrion. As written, it is probably
(a) a catabolic reaction (b) an anabolic reaction (c) an amphibolic reaction (d) we don’t have enough information to answer.