Metabolism Flashcards
What is metabolism?
With the term metabolism, all chemical reactions involved in maintaining the living state of the cells and the organism are described.
- Catabolism – breakdown of molecules to obtain energy
- Anabolism – synthesis of all compound needed by the cell
Metabolism in synthesis is the breakdown of nutrients in simpler molecules that used to produce energy, which is then used by the body for other things (synthesis of macromolecules etc..).
What is meant for equilibrium? And for steady state?
Equilibrium is the state that is reached when the concentration of reactants and products are constant over time, thus there’s no net rate.
Steady state is the state that is reached when state variables are constant over time, while having a flow through the system. This means that the rate of consumption of the reactants is equal to the rate of production of the products.
Can we make a balance for a variable of a system?
yes:
(V is the variable; e is the exchange of the variable between system and environment; i is the process inside the system that produce/consume the variable)
ΔV= ΔeV+ΔiV
What are some examples of Steady states in the human body?
- Glucose in system blood
- Glucose in system liver
- Metabolic pathways
How is metabolism regulated and controlled?
The general concept of regulation of metabolism is “enzymes control every pathway by increasing or decreasing its response to a signal”; this enzymes can be regulated, affecting their activity.
This activity is translated as the enzymatic rate. This rate can be regulated in three ways:
- Metabolic regulation – change in the concentration of the substrate, products or allosteric regulators. (intracellular)
- Post-translational modifications – change in the kinetic parameters of the enzyme. (inter-organ)
- Protein expression regulation – change in the number of enzymes. (intracellular)
v=kcat[E]([S]/{[S]+Km}) with this formula all three mechanisms are regulating enzymatic rate (v): post-translational modifications (1.) (kcat), gene expression (3.) ([E]), metabolic/allosteric regulation (2.) ([S]/{[S]+Km})
Another way to regulate metabolism is to regulate metabolic flux, with the help of iso-enzymes: this enzymes catalyse all the same reaction but have different forms and affinity.
Regulation occur at multiple levels:
- Intrinsic regulation – reactions self-regulate to respond to changes in the levels of substrates or products (feedback mechanism)
- Extrinsic regulation – change in metabolism in response to signals from other cells (hormones or growth factors).
In the postprandial state (after a meal) the nutrients are absorbed and broken down into simpler molecules (catabolism): nutrients (glycogen, protein mass, fats) are stored; insulin is high, glucagon is low.
In the basal state (overnight fast) metabolism change, to spare carbohydrates and increase reliance on fat as a substrate for energy supply: stored nutrients are mobilized (glycogen -> glucose; protein -> glucose; fat ->energy); insulin is low, glucagon is rising.
Some enzymes required for metabolism are irreversible: their ΔG is too low (extremely spontaneous process) that reverse it would need an incredible high amount of energy. This enzymes are used as pumps.
Give an overview of Glycolysis.
Glycolysis is the universal pathway to convert glucose into pyruvate.
It can be divided in two parts:
Phase I – preparative phase. In this phase key molecules for metabolic pathways are formed, by energy consumption: 2ATP are used, one when forming G6P (glucose-6-phosphate) and the other one when forming FBP from F6P.
Phase II – ATP-generating phase. In this phase energy and pyruvate are produced: 4ATP and 2PYR are produced per glucose molecule.
Each reaction is catalysed by an enzyme, but the most important one is phosphofructokinase (PFK) which catalyse the formation of fructose-1,6-biphophate. PFK is regulated by ATP via negative feedback: when ATP is abundant in the cell, ATP itself inhibit the enzyme, stopping the production of FBP
Give an overview of Gluconeogenesis.
Gluconeogenesis is the process that transform non-carbohydrate substrates into glucose.
Important steps in the synthesis of glucose are:
1. Conversion of PYR into PEP (phosphoenolpyruvate) via various enzymes. The intermediate metabolites (oxaloacetate and malate)of this conversion are part of other pathways.
2. Conversion of G6P into glucose, via glucose-6-phosphatase.
This two nodes are extremely important because they should be irreversible reactions, due to their very low ΔG, thus should not be possible to re-convert the previous reactant: this can be possible due to new enzymes used, that are able to reverse the reaction.
In the first conversion, the second intermediate metabolite (malate) is essential in the transfer of metabolism from the cytoplasm to the mitochondria: oxaloacetate can’t go through the mitochondria membrane, thus is converted into malate, which easily pass through the membrane, and then is converted back into oxaloacetate, since it is the metabolite needed for production of PEP. The opposite (oxaloacetate is transported back into the cytoplasm) can occur, but this time instead of malate, aspartate is produced as intermediate metabolite: this whole process is called malate aspartate shuttle.
Gluconeogenesis is regulated via various mechanism:
- negative feedback of PYR by Acetyl-CoA
- substrate level regulation of G6P
Give me an overview of Glycogen.
Glycogen is a key molecule for the storage of glucose: the liver is the main storage-organ, which contain glucose in the form of glycogen bubbles needed for the blood glucose homeostasis.
Glycogen does not have a linear structure, but is a very branched molecule: this is because branches increase the amount of glucose molecules bound to each other, allowing more sites of conversion.
Glycogen is synthesised and degraded when needed:
1. synthase is the enzyme responsible for its synthesis.
2. phosphorylase is the enzyme responsible for its mobilisation (degradation).
Glycogenolysis occur in the liver and in the muscles:
- liver: the presence of either glucagon has a positive forward effect on PKA, thus is activated, which will activate, also via positive forward effect, glycogen phosphorylase starting breaking glycogen, and at the same time, PKA will inhibit, via negative feedback, glycogen synthase . On the opposite hand, insulin have a negative feedback effect on glycogen phosphorylase, inhibiting it, but has a positive forward effect on glycogen synthase, which will start glycogen synthesis, while inhibiting PKA.
- muscles: the response to insulin and epinephrine is the same that occur in the liver in response to insulin and glucagon, but in muscles glycogenolysis is also affected by Ca2+.
Give me an overview of the Krebs cycle.
The Krebs cycle (also called TriCarboxylic Acid TCA cycle) is a series of chemical reactions that release stored energy through the oxidation of Acetyl-CoA derived from carbohydrates, fats and proteins.
The TCA cycle is a central driver of cellular respiration: all its intermediates are conserved throughout the cycle. This is due the fact that TCA cycle forms many starting points of other metabolic pathways:citrate is used in the fatty acid synthesis, α-ketoglutarate is used both in the amino acid synthesis and as neurotransmitter, succinyl CoA is used in the heme synthesis, malate is used in the gluconeogenesis and oxaloacetate is used in the amino acid synthesis.
An important step of the TCA cycle is actually the conversion of PYR into Acetyl-CoA: from a 3-carbon molecule to a 2-carbon molecule. This conversion is essential because it is impossible to make glucose from Acetyl-Coa (2C) making this reaction irreversible. This reaction is catalysed by PDH (pyruvate dehydrogenase).
PDH is a large and complex molecule, which function is the conversion of PYR into Acetyl-CoA:
PYR + CoA-SH + NAD+ –> CO2 + acetyl-CoA + NADH + H+
Since this reaction does not occur all at once, it is often used PDC (pyruvate dehydrogenase complex) instead of simple PDH.
PDC is highly regulated by both allosteric control and phosphorylation:
- Allostery: PDC is activated by FBP and inhibited by NADH and Acetyl-CoA.
- Phosphorylation: PDH kinase phosphorylate PDH causing its deactivation. In turn, the kinase is allostericly activated by NADH and deactivated by ADP, NAD+ and free coenzyme A. PDH phosphatase remove the phosphate, causing the activation of the complex. Ca2+ activate PDH phosphatase
Give an overview of the Pentose Phosphate Pathway.
The PPP (Pentose Phosphate Pathway) generates NADPH and riboses, while shunting carbons back to glycolysis and gluconeogenesis.
The PPP starts from G6P produced during glycolysis, which is converted into R5P (ribose-5-phosphate), while converting NADP+ into NADPH.
R5P is found in nucleotides while NADPH is essential for fatty acid synthesis, glutathione reduction and other reactions such as detoxification.
The PPP is divided in two parts:
- the oxidative part: generate NADPH while converting G6P into R5P and releasing carbon dioxide.
- the non-oxidative part: shunt carbons back to glycolysis, taking them from R5P and bringing to F6P and G3P (glyceraldehyde-3-phosphate)
Glucose-6-phosphate dehydrogenase is the major control point for the rate of NADPH synthesis and it is regulated by two mechanisms:
1. negative feedback by NADPH
2. negative feedback of Acetyl-CoA
For the regulation of the non-oxidative part of the PPP, no enzymes are needed: all reactions are closed to equilibrium, due to being freely reversible, causing what it is called “mass flow”.
Why glucose can’t be made from fatty acids?
Fatty acids derive from Acetyl-CoA, via fatty acid synthase. The impossibility of the conversion of fatty acids to glucose is due to the irreversibility of the reaction from PYR to Acetyl-CoA.
Why are fats important?
Fatty acids are important for:
- form healthy cell membranes (phospholipids)
- proper development an functioning of the brain and nervous system (ketone bodies)
- Storage of energy (TAG)
What is the human starvation response?
1st: glycogen. Glycogen is the main source of glucose.
2nd: proteins.
3rd: ketone bodies
What are ketone bodies?
Ketone bodies are substances produced by the liver during gluconeogenesis. Their role is to replace glucose as the main fuel of the brain in situations of glucose scarcity.
