Biochemistry- principles of metabolic regulation Flashcards
What is the need for metabolic regulation
The human body is composed of many organs and tissues, each with its own metabolic functions and needs.
Humans experience a variety of metabolic conditions, every single cell must have its basis needs met.
At a local level, each cell is capable of responding to some basic changes in the external environment, in order to maintain a
reasonably constant internal state.
From a wider perspective, the various organs work together to minimise changes to the internal environment, and their
different activities must be coordinated as a group despite their different locations and metabolic characteristics.
What are regulatory enzymes in metabolic regulations
Regulatory enzymes are the ones whose activity limits the rate of flux through the pathway.
They are often found at the beginning or just after branch points.
Sometimes controlled in several ways. Some of these controls act over the short term, others act over longer periods. This
will depend on how rapidly the pathway needs to adjust.
Describe the regulation of proteins
Transporters are also controlled in order to regulate metabolic pathways.
Proteins are regulated at several levels: transcription, mRNA stability, translation, degradation, location, covalent
modification, allosteric control.
Regulation of transcription, mRNA stability, translation and degradation affects [enzyme], and may take a longer time to
show an effect, but the effect may also be longer lasting.
Location, covalent modification and allosteric control of short term regulations of protein.
What are the slow vs fast methods in regulation
Some metabolic situations have advance warnings (e.g. puberty).
Would be a waste to synthesise proteins that would not be needed for a long time.
Others change within seconds (e.g. rest to exercise transition).
In these cases, waiting for the processes of transcription, translation, processing etc. would take a long time, so the proteins
are made, but made inactive until needed.
The type of regulation used is a good indication of the immediacy with which the protein must respond to metabolic
challenges.
Describe the regulated procedures: transcription, mRNA stability, translation, degradation, turnover, location and covalent modificaition
Transcription
In multicellular organisms, most cells contain the full complement of DNA, but will only transcribe a subset of genes,
relevant to their function.
The effect is crucial, it allows cells to behave entirely differently, in the same situation.
Cells may express different receptors for hormones, or different versions of the same enzyme, so that metabolic pathways
can be regulated differently.
The changes in transcription for a particular cell over time also plays a large role in regulation.
2.2. mRNA stability
Because each mRNA can be translated multiple times, regulating the rate at which the mRNA is degraded also has an effect
on the [protein].
2.3. Translation
Regulation of mRNA translation is another point at which the [protein] can be controlled.
2.4. Degradation
Proteins can be tagged by ubiquitin, which targets them for degradation in 26S proteasomes. Some proteins are broken
down in lysosomes. Either way, degradation is a permanent way of inactivating an enzyme.
Turnover
The constant processes of transcription, translation and degradation of proteins mean that proteins are in a constant state
of turnover.
Different proteins have different half-lives (ranging from 11 mins to the life of the organism).
The [protein] with short half-lives (such as those involved in metabolic regulation) can be quickly increased or decreased in
order to meet the needs of the cell.
Example: halting degradation of a protein with a short half-life will quickly increase its concentration, while halting the
production, will quickly decrease its concentration.
Location
In order to be effective, proteins must be in the correct location. This applies to both transporters and enzymes.
It may take seconds/or minutes for this effect to take place.
Covalent modification
Covalent modification of proteins is a stable way of altering a protein’s behaviour.
Both the modification and its undoing are enzyme catalysed.
Examples: phosphorylation, adenylation, ADP-ribosylation.
Phosphorylation is the most common, occurring mostly on the hydroxyl of
serine residues, but also threonine and tyrosine.
The effects of covalent modification are seen within seconds to minutes.
Up to half of a cell’s proteins can be modified by phosphorylation.
o Phosphorylation is catalysed by protein kinases. Cascades of
phosphorylation play an important role in the signal amplification
of many hormones. Phosphorylation may activate or inhibit
proteins.
o Dephosphorylation by phosphoprotein phosphatases.
Kinases and phosphatases have target sequences that can be found on many proteins.
Phosphorylation may activate or inhibit proteins.
Describe allosteric control and allosteric inhibitors
Involves the reversible, non-covalent binding of effectors, to enzymes, resulting in activation or inhibition.
The effects are seen in seconds (or ms).
Allosteric proteins are in equilibrium between a T state (tense, does not bind to substrate well)
and an R state (relaxed, binds substrate easily, a more effective catalyst).
Allosteric effectors can affect Vmax, Km or both.
Competitive inhibitors: increase Km but not Vmax. Allosteric
inhibitors that prevent the enzyme binding to the substrate are
classed as competitive inhibitors, as the enzyme can only bind to
one of the inhibitor or substrate.
Non-competitive inhibitor: decreases Vmax. It binds to E and E:S
(the effect being the same as decreasing [enzyme].
Types of allosteric control:
Several types of allosteric control by substrates are seen in metabolic
pathways, allowing the rate of the pathway to be controlled, and also to
be responsive to the rate of other metabolic pathways.
Feedback inhibition: the product inhibits the enzyme, which is useful
when you don’t want to make too much product
Feedforward activation: the [product] increases. Increasing [substrate] activates enzymes later in the pathway to process
the product.
What are the different action types for hormones?
Hormones are crucial for co-ordinating metabolic responses, allowing cells to communicate to others on how to behave in
certain situations.
Hormones can be defined by the distance over which they act:
o Endocrine: acts on cells far from the site of release.
Example: insulin, adrenaline.
o Paracrine: acts on nearby cells.
Example: immune responses.
o Autocrine: act on the cell that released the hormone.
Example: T cells and interleukine-2.
Cells express receptors to specific hormones, and the intracellular section of the receptor determines how the cell will
respond to the hormone
Describe the mechanism of signal transduction
[1] Hormone is released and a corresponding receptor is present.
[2] Hormone binds to the receptor.
[3] Intracellular domain changes, and an enzyme increases the
concentration of a second messenger within the cell, which goes onto
affect other enzymes.
[4] Signal needs to eventually be toned down/inhibited.
[5] Signal is shut down, the hormone concentration decreases and the cell desensitises.
Describe the slow and fast responses to hormones
Some hormones, such as oestrogen have effects that typically manifest over a relatively long period of time.
These will normally involve the stimulation/inhibition of transcription factors, which bind to particular DNA sequences
(response elements) and alter the behaviour of the transcription machinery towards nearby genes.
Others manifest their effects relatively quickly, over seconds or hours. In these cases, it is normally enzymes whose activity
is altered.
Some hormones, such as insulin and glucagon, work in both ways. Therefore, there hormones can direct short term
responses to glucose fluctuations, but also direct preparation for consistently high/low sugar diet.
