Adenylate Energy ChargeAdenylate Energy Charge

Some enzymes respond to absolute concentration, Some enzymes respond to absolute concentration, but most respond to ratios. but most respond to ratios.

Dan Atkinson introduced the concept ofDan Atkinson introduced the concept of ENERGY ENERGY CHARGECHARGE in 1968 to summarize the energy status in 1968 to summarize the energy status

of a cell. of a cell.

It is a measure of the relative concentration of high-It is a measure of the relative concentration of high-energy phosphoenergy phospho - anhydride bonds available in the - anhydride bonds available in the

adenylate pooladenylate pool. .

The adenylate energy charge, or The adenylate energy charge, or AECAEC,, has the has the range 0 to 1.0. If all the adenylate is in the form of range 0 to 1.0. If all the adenylate is in the form of ATP, AEC = 1.0, and the potential for phosphoryl ATP, AEC = 1.0, and the potential for phosphoryl

transfer is maximal.transfer is maximal.

At the other extreme, if AMP is the only adenylate At the other extreme, if AMP is the only adenylate form present, form present, AECAEC = 0. = 0.

Then the relative amounts of the three adenine Then the relative amounts of the three adenine nucleotides are fixed by the energy charge. The nucleotides are fixed by the energy charge. The

following figure shows the relative changes in the following figure shows the relative changes in the concentrations of the adenylates as energy charge concentrations of the adenylates as energy charge

varies from 0 to 1.0.varies from 0 to 1.0.

Regulatory enzymes in energy-producing Regulatory enzymes in energy-producing catabolic pathways show greater activity at catabolic pathways show greater activity at low energy charge, but the activity falls off low energy charge, but the activity falls off

sharbly as sharbly as AECAEC approaches 1.0. approaches 1.0.

In contrast, regulatory enzymes of anabolic In contrast, regulatory enzymes of anabolic sequences are not very active at low energy sequences are not very active at low energy charge, but their activities increase as charge, but their activities increase as AECAEC

nears 1.0 .nears 1.0 .

These contrasting responses are termed These contrasting responses are termed RR, for , for ATP-regenerating, and ATP-regenerating, and UU, for ATP-utilizing. , for ATP-utilizing.

Regulatory enzymes such as Regulatory enzymes such as PFKPFK and pyrvuate and pyrvuate kinase in glycolysis follow the kinase in glycolysis follow the RR response response

curve as curve as AECAEC is varied. is varied.

Note that PFK itself is an ATP-utilizing Note that PFK itself is an ATP-utilizing enzyme, using ATP to phosphorylate fructosenzyme, using ATP to phosphorylate fructosee--

6-phosphate to yield fructos6-phosphate to yield fructosee-1,6-bisphosphate. -1,6-bisphosphate. Nevertheless, because PFK acts physiologically Nevertheless, because PFK acts physiologically as the valve controlling the flux of carbohydrate as the valve controlling the flux of carbohydrate

down the catabolic pathways of cellular down the catabolic pathways of cellular respiration that lead to ATP regeneration, it respiration that lead to ATP regeneration, it

responds as an “responds as an “RR” enzyme to energy charge.” enzyme to energy charge.

Regulatory enzymes in anabolic Regulatory enzymes in anabolic pathways, such as acetyl-CoA pathways, such as acetyl-CoA

carboxylase, which initiates fatty acid carboxylase, which initiates fatty acid biosynthesis, respond as biosynthesis, respond as ““UU”” enzymes. enzymes.

Cellular energy homoeostasis: maintenance of Cellular energy homoeostasis: maintenance of energy state by creatine kinase (CK) and energy state by creatine kinase (CK) and

adenylate kinase (AK) isoenzymesadenylate kinase (AK) isoenzymes

A fundamental principle in multicellular A fundamental principle in multicellular organisms is the strict maintenance of organisms is the strict maintenance of

stable concentrations of intracellular stable concentrations of intracellular oxygenoxygen and and ATPATP asas the universal energy the universal energy

currency of biological systems, as well as currency of biological systems, as well as the tight regulation of energy utilization the tight regulation of energy utilization

with energy supply.with energy supply.

Upon activation of excitable cells, such as skeletal Upon activation of excitable cells, such as skeletal and cardiac muscle, or brain and nerve cells, ATP and cardiac muscle, or brain and nerve cells, ATP

turnover rates may increase by several orders of turnover rates may increase by several orders of magnitude within seconds, but [ATP] remains magnitude within seconds, but [ATP] remains

remarkably stable and ATP/ADP ratios, as well as remarkably stable and ATP/ADP ratios, as well as ATP/AMP ratios, are maintained as high as possible ATP/AMP ratios, are maintained as high as possible to guarantee optimal efficiency for cellular ATPases to guarantee optimal efficiency for cellular ATPases

that are at work to perform a multitude of energy-that are at work to perform a multitude of energy-dependent cellular activities, such as muscle dependent cellular activities, such as muscle

contraction, cell motility and ion pumping.contraction, cell motility and ion pumping.

concerted action of kinases involved in concerted action of kinases involved in energy homoeostasisenergy homoeostasis

ATP homoeostasis and maintenance of high ATP homoeostasis and maintenance of high ATP/ADP and ATP/AMP ratios are facilitated by ATP/ADP and ATP/AMP ratios are facilitated by

the action of two well-known enzyme systems, the action of two well-known enzyme systems, working as very fast and efficient energy working as very fast and efficient energy

safeguards. First, CKs, efficiently regenerating safeguards. First, CKs, efficiently regenerating ATP at the expense of phosphocreatine (PCr) ATP at the expense of phosphocreatine (PCr)

by the following reaction.by the following reaction.

PCr+ADPPCr+ADP ATP+Cr ATP+Cr

Second, Adenylate kinase (AK), Second, Adenylate kinase (AK), reconverting two ADP molecules into one reconverting two ADP molecules into one

ATP and one AMP.ATP and one AMP.

These two enzymes, working together in These two enzymes, working together in an subcellular energy distribution network an subcellular energy distribution network

or circuitor circuit temporally and, due to their temporally and, due to their subcellular microcompartmentation, to subcellular microcompartmentation, to

buffer subcellular ATPbuffer subcellular ATP level.level.

A common cause of many diseases, like A common cause of many diseases, like cardiac insufficiency, cardiac hypertrophy as cardiac insufficiency, cardiac hypertrophy as

well as most of the neurodegenerative well as most of the neurodegenerative pathologies, is a generally lowered cellular pathologies, is a generally lowered cellular PCr/ATP ratio, indicating a lowered energy PCr/ATP ratio, indicating a lowered energy

state of cells and tissues.state of cells and tissues.

This is often accompanied by elevated calcium This is often accompanied by elevated calcium levels, leading to chronic calcium overload with levels, leading to chronic calcium overload with

its host of negative consequences on cell its host of negative consequences on cell function and viability.function and viability.