High Energy Compounds

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• High Energy Compounds

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• ATP often serves as an energy source.
• Hydrolytic cleavage of one or both of the "high
  energy" bonds of ATP is coupled to an
  energy-requiring (non-spontaneous)
  reaction. (Examples presented earlier.)
• AMP functions as an energy sensor regulator of
  metabolism.
• When ATP production does not keep up with needs,
  a higher portion of a cell's adenine nucleotide
  pool is AMP.
• AMP stimulates metabolic pathways that produce
  ATP.
• Some examples of this role involve direct
  allosteric activation of pathway enzymes by AMP.
• Some regulatory effects of AMP are mediated by
  the enzyme AMP-Activated Protein Kinase.

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High energy bonds

• Phosphoanhydride bonds (formed by splitting out
  H2O between 2 phosphoric acids or between
  carboxylic phosphoric acids) have a large
  negative ?G of hydrolysis.

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• Why do phosphoanhydride linkages have a high DG
  of hydrolysis? Contributing factors for ATP PPi
  include
• Resonance stabilization of products of hydrolysis
  exceeds resonance stabilization of the compound
  itself.
• Electrostatic repulsion between negatively
  charged phosphate oxygen atoms favors
  separation of the phosphates.

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• Compounds with ? G more negative than 7 Kcal/mole
  or 30 KJ/ mole are regarded as high energy
  compounds.

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ATP has special roles in energy coupling Pi
transfer. DG of phosphate hydrolysis from ATP is
intermediate among examples below. ATP can thus
act as a Pi donor, ATP can be synthesized by Pi
transfer, e.g., from PEP.
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Roles of "high energy" bonds

• Energy transfer or storage
• ATP, PPi, polyphosphate, phosphocreatine
• Group transfer
• ATP, Coenzyme A
• Transient signal
• cyclic AMP

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Examples of other high energy compounds
1- Phosphocreatine another compound with a
"high energy" phosphate linkage, is used in nerve
muscle for storage of P bonds.

• Phosphocreatine is produced
• when ATP levels are high.
• When ATP is depleted during
• exercise in muscle, phosphate is
• transferred from phosphocreatine
• to ADP, to replenish ATP.

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• 2- Phosphoenolpyruvate (PEP), involved in ATP
  synthesis in Glycolysis, has a very high ?G of Pi
  hydrolysis.
• Removal of Pi from ester linkage in PEP is
  spontaneous because the enol spontaneously
  converts to a ketone.
• The ester linkage in PEP is an exception.

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3- A thioester forms between a carboxylic acid
a thiol (SH), e.g., the thiol of coenzyme A.
Thioesters are linkages. In contrast to
phosphate esters, thioesters have a large
negative DG of hydrolysis.
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• Kinetics vs Thermodynamics

• A high activation energy barrier usually causes
  hydrolysis of a high energy bond to be very
  slow in the absence of an enzyme catalyst.
• This kinetic stability is essential to the role
  of ATP and other compounds with bonds.
• If ATP would rapidly hydrolyze in the absence of
  a catalyst, it could not serve its important
  roles in energy metabolism and phosphate
  transfer.
• Phosphate is removed from ATP only when the
  reaction is coupled via enzyme catalysis to some
  other reaction useful to the cell, such as
  transport of an ion, phosphorylation of glucose,
  or regulation of an enzyme by phosphorylation of
  a serine residue.

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Adenylate Energy Charge

• Many reactions in metabolism are controlled by
  the energy status of the cell.
• One index of the energy status is the energy
  charge, which is proportional to the mole
  fraction of ATP plus half the mole fraction of
  ADP, given that ATP contains two anhydrid bonds
  whereas ADP contains one.
• It is a measure of the relative concentration of
  high-energy phospho - anhydride bonds available
  in the adenylate pool.
• The energy charge can have a value ranging from 0
  (all AMP) to 1 (all ATP).

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Cont

• Hence the energy charge is defined as
• Energy charge ATP1/2ADP
• Adenylate Kinase catalyze the following
  reactions
• 1- ATP ADP Pi
• 2- ATP AMP PPi
• 3- ATPAMP 2ADP

• ATP ADP AMP

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Cont

• Danil Atkinson showed that ATP-generating
  pathways (catabolic) are inhibited by a high
  energy charge.
• It is evident that control of these pathways has
  evolved to maintain the energy charge within
  rather narrow limits. In other words the energy
  charge like the pH of a cell is buffered. The
  energy charge of most cells range from 0.8 to
  0.95.
• A high Energy Charge signals the slow down of
  metabolism. A low Energy Charge signals up
  regulation of metabolism.

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Energy charge regulate metabolism

High concentrations of ATP inhibit the relative
rates of a typical ATP-generating (catabolic)
pathway and stimulate the typical ATP-utilizing
(anabolic) pathway.
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• Regulatory enzymes in energy-producing catabolic
  pathways show greater activity at low energy
  charge, but the activity falls off sharply as AEC
  approaches 1.0.
• In contrast, regulatory enzymes of anabolic
  sequences are not very active at low energy
  charge, but their activities increase as AEC
  nears 1.0 .
• These contrasting responses are termed R, for
  ATP-regenerating, and U, for ATP-utilizing.

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• Regulatory enzymes such as PFK and pyrvuate
  kinase in glycolysis follow the R response curve
  as AEC is varied.
• Note that PFK itself is an ATP-utilizing enzyme,
  using ATP to phosphorylate fructose-6-phosphate
  to yield fructose-1,6-bisphosphate. Nevertheless,
  because PFK acts physiologically as the valve
  controlling the flux of carbohydrate down the
  catabolic pathways of cellular respiration that
  lead to ATP regeneration, it responds as an R
  enzyme to energy charge.

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• Regulatory enzymes in anabolic pathways, such as
  acetyl-CoA carboxylase, which initiates fatty
  acid biosynthesis, respond as U enzymes.

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Cellular energy homoeostasis maintenance of
energy state by creatine kinase (CK) and
adenylate kinase (AK) isoenzymes

• A fundamental principle in multicellular
  organisms is the strict maintenance of stable
  concentrations of intracellular oxygen and ATP as
  the universal energy currency of biological
  systems, as well as the tight regulation of
  energy utilization with energy supply.

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• Upon activation of excitable cells, such as
  skeletal and cardiac muscle, or brain and nerve
  cells, ATP turnover rates may increase by several
  orders of magnitude within seconds, but ATP
  remains remarkably stable and ATP/ADP ratios, as
  well as ATP/AMP ratios, are maintained as high as
  possible to guarantee optimal efficiency for
  cellular ATPases that are at work to perform a
  multitude of energy-dependent cellular
  activities, such as muscle contraction, cell
  motility and ion pumping.

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• ATP homoeostasis and maintenance of high ATP/ADP
  and ATP/AMP ratios are facilitated by the action
  of two well-known enzyme systems, working as very
  fast and efficient energy safeguards. First, CKs,
  efficiently regenerating ATP at the expense of
  phosphocreatine (PCr) by the following reaction
• PCr ADP ATP Cr

CKs
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• Second, Adenylate kinase (AK), reconverting two
  ADP molecules into one ATP and one AMP.
• These two enzymes, working together in an
  subcellular energy distribution network or
  circuit temporally and, due to their subcellular
  microcompartmentation, to buffer subcellular ATP
  level.

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• A common cause of many diseases, like cardiac
  insufficiency, cardiac hypertrophy as well as
  most of the neurodegenerative pathologies, is a
  generally lowered cellular PCr/ATP ratio,
  indicating a lowered energy state of cells and
  tissues.
• This is often accompanied by elevated calcium
  levels, leading to chronic calcium overload with
  its host of negative consequences on cell
  function and viability.