Gluconeogenesis is the process by which glucose is synthesized from non-carbohydrate precursors in the liver and kidneys. It occurs mainly during periods of fasting and involves converting substrates like lactate, glycerol, and certain amino acids into glucose. The pathway overcomes three thermodynamic barriers of glycolysis through smaller successive steps. Regulation occurs through allosteric control of enzymes, hormonal control of fructose 2,6-bisphosphate levels, and transcriptional control of key genes like PEPCK and FOXO1. Together these mechanisms help direct carbon fluxes towards gluconeogenesis or glycolysis based on energy demands.
Gluconeogenesis- Steps, Regulation and clinical significanceNamrata Chhabra
Gluconeogenesis- Thermodynamic barriers, substrates of gluconeogenesis, reciprocal regulation of glycolysis and gluconeogenesis, biological and clinical significance
Glycogenolysis, process by which glycogen, the primary carbohydrate stored in the liver and muscle cells of animals, is broken down into glucose to provide immediate energy and to maintain blood glucose levels during fasting. These slides will provide you detail explanation of Glycogenolysis.
Gluconeogenesis- Steps, Regulation and clinical significanceNamrata Chhabra
Gluconeogenesis- Thermodynamic barriers, substrates of gluconeogenesis, reciprocal regulation of glycolysis and gluconeogenesis, biological and clinical significance
Glycogenolysis, process by which glycogen, the primary carbohydrate stored in the liver and muscle cells of animals, is broken down into glucose to provide immediate energy and to maintain blood glucose levels during fasting. These slides will provide you detail explanation of Glycogenolysis.
Pentose phosphate pathway is also called Hexose monophosphate pathway/ HMP shunt/ Phosphogluconate pathway.
It is an alternative route for the metabolism of glucose.
It is more complex pathway than glycolysis.
It is more anabolic in nature.
It takesplace in cytosol.
The tissues such as liver, adipose tissue, adrenal gland, erythrocytes,testes and lactating mammary gland are highly active in HMP shunt.
It concern with the biosynthesis of NADPH and pentoses.
Lipid metabolism is the synthesis and degradation of lipids in cells.
It involves the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes.
In animals, these fats are obtained from food or synthesized by the liver.
Pentose phosphate pathway is also called Hexose monophosphate pathway/ HMP shunt/ Phosphogluconate pathway.
It is an alternative route for the metabolism of glucose.
It is more complex pathway than glycolysis.
It is more anabolic in nature.
It takesplace in cytosol.
The tissues such as liver, adipose tissue, adrenal gland, erythrocytes,testes and lactating mammary gland are highly active in HMP shunt.
It concern with the biosynthesis of NADPH and pentoses.
Lipid metabolism is the synthesis and degradation of lipids in cells.
It involves the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes.
In animals, these fats are obtained from food or synthesized by the liver.
intro of glycolysis there cycle and step - function-significance-defination-glucogenesis cycle-significance of gluconeogenesis-function of gluconeogenesis-conclusion
This PPT contains content of Gluconeogenesis, Steps involved in Gluconeogenesis, (Gluconeogenesis from Pyruvate, Gluconeogenesis from lactate, Gluconeogenesis from amino acids, Gluconeogenesis from glycerol, Gluconeogenesis from Propionate), Regulation and significance of Gluconeogenesis
Carbohydrates are the sugars, starches and fibers found in fruits, grains, vegetables and milk products. Though often maligned in trendy diets, carbohydrates — one of the basic food groups — are important to a healthy diet.
To understand how the glycolytic pathway is converts glucose to pyruvate.
To understand conservation of chemical potential energy in the form of ATP and NADH.
To learn the intermediates, enzyme, and cofactors of the glycolytic pathway.
An enzyme is a substance that acts as a catalyst in living organisms, regulating the rate at which chemical reactions proceed without itself being altered in the process. The biological processes that occur within all living organisms are chemical reactions, and most are regulated by enzymes
The aqueous humour is a transparent, watery fluid similar to plasma, but containing low protein concentrations. It is secreted from the ciliary epithelium, a structure supporting the lens
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. The cornea, with the anterior chamber and lens, refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power.
Lens is a transparent, biconvex, crystalline structure placed between iris and the vitreous in a saucer-shaped depression, the patellar fossa. The lens is a crystalline structure that is avascular and is devoid of nerves and connective tissue
It consists of three distinct part:
Lens capsule
Anterior lens epithelium, and
Lens substance or lens fibres
Small amounts of vitamins are required in the diet to promote growth, reproduction, and health. Vitamins A, D, E, and K are called the fat-soluble vitamins, because they are soluble in organic solvents and are absorbed and transported in a manner similar to that of fats.
Water soluble vitamins include Vitamin C and the vitamin B complex: thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), Vitamin B6, biotin (B7), folic acid (B9), Vitamin B12. Vitamin A in its Beta-Carotene form is also water-soluble.
The tear film is a complex mixture of substances secreted from multiple sources on the ocular surface, including the lacrimal gland, the accessory lacrimal glands, the meibomian glands, and the goblet cells.
A picornavirus is a virus belonging to the family Picornaviridae, a family of viruses in the order Picornavirales. Vertebrates, including humans, serve as natural hosts. Picornaviruses are nonenveloped viruses that represent a large family of small, cytoplasmic, plus-strand RNA viruses with a 30-nm icosahedral capsid.
Poxviruses are brick or oval-shaped viruses with large double-stranded DNA genomes. Poxviruses exist throughout the world and cause disease in humans and many other types of animals. Poxvirus infections typically result in the formation of lesions, skin nodules, or disseminated rash.
Leptospirosis is a bacterial disease that affects humans and animals. It is caused by bacteria of the genus Leptospira. In humans, it can cause a wide range of symptoms, some of which may be mistaken for other diseases. Some infected persons, however, may have no symptoms at all.
The human immunodeficiency virus (HIV) is a lentivirus (a subgroup of retrovirus) that causes HIV infection and over time acquired immunodeficiency syndrome (AIDS).
Treponema is a genus of spiral-shaped bacteria. The major treponeme species of human pathogens is Treponema pallidum, whose subspecies are responsible for diseases such as syphilis, bejel, and yaws.
Haemophilus is the name of a group of bacteria. There are several types of Haemophilus. They can cause different types of illnesses involving breathing, bones and joints, and the nervous system. One common type, Hib (Haemophilus influenzae type b), causes serious disease. It usually strikes children under 5 years old
Moraxella is a genus of Gram-negative bacteria in the Moraxellaceae family. It is named after the Swiss ophthalmologist Victor Morax. The organisms are short rods, coccobacilli, or as in the case of Moraxella catarrhalis, diplococci in morphology, with asaccharolytic, oxidase-positive, and catalase-positive properties
Pseudomonas is a type of bacteria that can cause infections. Pseudomonas is a common genus of bacteria, which can create infections in the body under certain circumstances. There are many different types of Pseudomonas bacteria
Neisseria gonorrhoeae is the obligate human pathogen that causes the sexually transmitted disease (STD) gonorrhea. This Gram-negative diplococci/gonococci does not infect other animals or experimental animals and does not survive freely in the environment. The gonococcal infection occurs in the upper or lower tract, pharynx, ophthalmic area, rectum, and bloodstream. During the 1980’s gonorrhea was also referred to as “the clap” when public awareness was quite minimal. This was one of the venereal diseases prostitutes hoped to contract since it resulted in infertility by pelvic inflammatory disease (PID). As documentation, diagnostic testing, and public awareness improved, there has been a decline in incidence reports, however, it is still considered a very common infectious disease.
Meningococci are a type of bacteria that cause serious infections. The most common infection is meningitis, which is an inflammation of the thin tissue that surrounds the brain and spinal cord. Meningococci can also cause other problems, including a serious bloodstream infection called sepsis. In its early stages, you may have flu-like symptoms and a stiff neck. But the disease can progress quickly and can be fatal. Early diagnosis and treatment are extremely important. Lab tests on your blood and cerebrospinal fluid can tell if you have it. Treatment is with antibiotics. Since the infection spreads from person to person, family members may also need to be treated.
A vaccine can prevent meningococcal infections.
Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae. Diphtheria causes a thick covering in the back of the throat. It can lead to difficulty breathing, heart failure, paralysis, and even death. CDC recommends vaccines for infants, children, teens and adults to prevent diphtheria. The presentation consists of basic concepts regarding the bacteria and its infection. It has explanation in detail about signs and symptoms of Diptheria
Contraindications, Adverse reactions and ocular nutritional supplementsArun Geetha Viswanathan
utritional supplements comprise a great deal of the products available over the counter in most pharmacies. Although most vitamin supplements are relatively harmless—except for the fat soluble ones A, D, E, and K—they are not the only supplements available to patients. Some of these other, non-vitamin supplements can actually be harmful to patients and often they have been proven to be ineffective. This doesn’t mean that patients will stop taking them though, which in turn leaves the potential for contraindications of nutritional supplements with prescription-based drugs wide open.
Ageing is a gradual process that takes place over many decades. Most theories of ageing relate to impaired DNA replication and loss of cell viability and hence the viability of the body’s organs. Ageing is often accompanied by socioeconomic changes that can have a great impact on the nutritional needs and status of elderly individuals. The incidence of disability increases with ageing, with over a third of the elderly population limited by chronic conditions and unable to carry on normal daily living activity
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
This pdf is about the Schizophrenia.
For more details visit on YouTube; @SELF-EXPLANATORY;
https://www.youtube.com/channel/UCAiarMZDNhe1A3Rnpr_WkzA/videos
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(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
The increased availability of biomedical data, particularly in the public domain, offers the opportunity to better understand human health and to develop effective therapeutics for a wide range of unmet medical needs. However, data scientists remain stymied by the fact that data remain hard to find and to productively reuse because data and their metadata i) are wholly inaccessible, ii) are in non-standard or incompatible representations, iii) do not conform to community standards, and iv) have unclear or highly restricted terms and conditions that preclude legitimate reuse. These limitations require a rethink on data can be made machine and AI-ready - the key motivation behind the FAIR Guiding Principles. Concurrently, while recent efforts have explored the use of deep learning to fuse disparate data into predictive models for a wide range of biomedical applications, these models often fail even when the correct answer is already known, and fail to explain individual predictions in terms that data scientists can appreciate. These limitations suggest that new methods to produce practical artificial intelligence are still needed.
In this talk, I will discuss our work in (1) building an integrative knowledge infrastructure to prepare FAIR and "AI-ready" data and services along with (2) neurosymbolic AI methods to improve the quality of predictions and to generate plausible explanations. Attention is given to standards, platforms, and methods to wrangle knowledge into simple, but effective semantic and latent representations, and to make these available into standards-compliant and discoverable interfaces that can be used in model building, validation, and explanation. Our work, and those of others in the field, creates a baseline for building trustworthy and easy to deploy AI models in biomedicine.
Bio
Dr. Michel Dumontier is the Distinguished Professor of Data Science at Maastricht University, founder and executive director of the Institute of Data Science, and co-founder of the FAIR (Findable, Accessible, Interoperable and Reusable) data principles. His research explores socio-technological approaches for responsible discovery science, which includes collaborative multi-modal knowledge graphs, privacy-preserving distributed data mining, and AI methods for drug discovery and personalized medicine. His work is supported through the Dutch National Research Agenda, the Netherlands Organisation for Scientific Research, Horizon Europe, the European Open Science Cloud, the US National Institutes of Health, and a Marie-Curie Innovative Training Network. He is the editor-in-chief for the journal Data Science and is internationally recognized for his contributions in bioinformatics, biomedical informatics, and semantic technologies including ontologies and linked data.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
2. Gluconeogenesis: an intro
• Defined as biosynthesis of glucose from non-carbohydrate
precursors.
• The major non-carbohydrate precursors are lactate, amino
acids, glycerol and the carbon skeletons of most amino
acids
• Non-carbohydrate precursors of glucose are first converted
into pyruvate or as oxaloacetate and DHAP
• When fasting, most of the body’s glucose needs must be
met by gluconeogenesis
• Occurs mainly in liver and to some extent in kidney
• Responsible for 64% of total glucose production over the
first 22 hours of the fast and accounts for almost all the
glucose production by 46 hours
4. Thermodynamic Barriers
• Gluconeogenesis is not reversal of glycolysis.
• There are three major thermodynamic barriers for the
pathway which are three irreversible steps in glycolysis
• These three major barriers are bypassed by successive
smaller steps with relatively lesser ΔG.
Glucose + ATP Glucose 6 – P + ADP
ΔG = -8.0 kcal/ mol (-33 kJ /mol)
Fructose 6 – P+ ATP Fructose 1, 6 – P + ADP
ΔG = -5.3 kcal/ mol (-22 kJ /mol)
Phosphoenolpyruvate+ ADP Pyruvate + ATP
ΔG = -4.0 kcal/ mol (-17 kJ /mol)
5. Pyruvate to Phosphoenolpyruvate
• Endergonic & requires free energy input.
• This is accomplished by first converting the pyruvate to
oxaloacetate, a “high-energy” intermediate
• Exergonic decarboxylation OAA provides the free energy
necessary for PEP synthesis.
• CO2 is added to pyruvate by pyruvate carboxylase
enzyme
• CO2 that was added to pyruvate to form OAA is released
in the reaction catalyzed by phosphoenolpyruvate
carboxykinase (PEPCK) to form PEP
• GTP provides a source of energy & phosphate group of
PEP.
6. Pyruvate to PEP
PYRUVATE CARBOXYLASE
•A tetrameric protein of
identical 130-kD subunits
•Has a biotin prosthetic
group.
•Biotin functions as a CO2
carrier by acquiring a
carboxyl substituent at its
ureido group
•Biotin is covalently bound
to the enzyme by an amide
linkage of Lys residue to
form a biocytin
7. Pyruvate to PEP
PHOSPHOENOLPYRUVATE CARBOXYKINASE
•OAA is converted to PEP by PEPCK.
•Mg2+-dependent reaction requires
GTP as the phosphoryl group donor
•Reaction is reversible under
intracellular conditions
8. • Δ G‘o = 0.9 kJ/mol (Vs -17 kJ/mol of glycolysis) for this
reaction which make the reaction quite reversible
• But actually the Δ G under cellular condition is strongly
negative due to very lesser concentration of PEP favoring
a forward way of reaction (-25 kJ/mol)
• Thus the reaction is strongly irreversible
PEP + ADP + GDP +Pi + CO2
Pyruvate to PEP (overall reaction)
Pyruvate + ATP + GTP +HCO-
3
9. Alternative pathways
•There are two pathways for
PEP synthesis.
• one route involve
movement of reduction
equivalents to the cytoplasm,
which provides balance
between NADH produced and
consumed in the cytosol.
•Another route is prominent
when lactate is a source
which yields NADH for
gluconeogenesis. Hence
conversion to Malate is
unnecessary.
10. Fructose 1,6-Bis P to Fructose 6-P
• This step is irreversible hydrolysis of fructose 1,6-
bisphosphate to fructose 6-phosphate and Pi.
• Fructose 1,6-bisphosphatase (FBPase-1) Mg 2+ dependent
enzyme catalyzes this exergonic hydrolysis.
• It is present in liver, kidney, and skeletal muscle, but is
probably absent from heart and smooth muscle.
• it is an allosteric enzyme that participates in the regulation of
gluconeogenesis.
• Δ G = - 16.3 kJ/mol (Vs -22 kJ /mol of glycolysis)
Fructose 6-phosphate + PiFructose 1,6-bisphosphate +H2O
11. Glucose 6-P to Glucose
• This final step in the generation of glucose does not take place in
the cytosol.
• Glucose 6-P is transported into the lumen of the endoplasmic
reticulum, where it is hydrolyzed to glucose by glucose 6-
phosphatase, which is bound to the membrane at the luminal
side.
• This compartmentalisation can only be seen in glucose
producing cells like hepatocytes, renal cells and epithelial cells of
small intestine
• An associated Ca2+ binding stabilizing protein is essential for
phosphatase activity.
• Glucose and Pi are then shuttled back to the cytosol by a pair of
transporters.
Glucose+ PiGlucose 6-phosphate +H2O
12. T1- transports glucose 6-phosphate into the lumen of the ER
T2- transport Pi to the cytosol
T 3 – transport glucose to the cytosol.
SP- Ca2+binding protein
The glucose transporter in the endoplasmic reticulum membrane
is like those found in the plasma membrane.
Glucose 6-P to Glucose
13. Energetics of gluconeogenesis
• Six nucleotide triphosphate molecules are hydrolyzed to synthesize
glucose from pyruvate in gluconeogenesis, whereas only two molecules of
ATP are generated in glycolysis in the conversion of glucose into pyruvate.
• Thus it is not a simple reversal of glycolysis but it is energetically an
expensive affair.
14. Substrates of gluconeogenesis
• The major substrates are the glucogenic amino acids, lactate, glycerol, and
propionate.
Entry of glucogenic amino acids
• Amino acids that are degraded to pyruvate, α-ketoglutarate, succinyl CoA,
fumarate, or oxaloacetate are termed glucogenic amino acids.
• The net synthesis of glucose from these amino acids is feasible because
these citric acid cycle intermediates and pyruvate can be converted into
phosphoenolpyruvate.
• Amino acids are derived from the dietary proteins, tissue proteins or from
the breakdown of skeletal muscle proteins during starvation.
• After transamination or deamination, glucogenic amino acids yield either
pyruvate or intermediates of the citric acid cycle
16. • In active skeletal muscle the rate of glycolysis
exceeds the rate of oxidative metabolism which leads
to anaerobic glycolysis in skeletal muscle
• During anaerobic glycolysis in skeletal muscle,
pyruvate is reduced to lactate by lactate
dehydrogenase (LDH).
• Lactate is readily converted into pyruvate by the
action of lactate dehydrogenase.
Entry of Lactate
17. • Propionate is a major precursor of
glucose in ruminants.
• It enters gluconeogenesis via the
citric acid cycle.
• In non-ruminants, including
humans, propionate arises from
the Beta -oxidation of odd-chain
fatty acids that occur in ruminant
lipids, as well as the oxidation of
isoleucine and the side-chain of
cholesterol, and is a (relatively
minor) substrate for
gluconeogenesis.
Entry of Propionate
18. • The hydrolysis of triacylglycerols in fat cells yields glycerol and
fatty acids.
• Glycerol may enter either the gluconeogenic or the glycolytic
pathway at DHAP
• In the fasting state glycerol released from lipolysis of adipose
tissue triacylglycerol is used solely as a substrate for
gluconeogenesis in the liver and kidneys.
Entry of Glycerol
Glycerol Kinase is absent in adipose tissue hence the formed glycerol is transported
to liver and used as per the need of the hour.
20. • Need of regulation
• There are three major types of regulation
– Allosteric regulation
– Hormonal Regulation
– Transcriptional Regulation
Regulation of gluconeogenesis
21. Allosteric regulation
• Phosphofructokinase-1 (PFK-1)
– Enzyme has several regulatory sites at which allosteric activators or
inhibitors bind
– ATP inhibits PFK-1 by binding to an allosteric site and lowering the
affinity of the enzyme for fructose 6-phosphate
– ADP and AMP act allosterically to relieve this inhibition by ATP.
– High citrate concentration increases the inhibitory effect of ATP.
– Thus glycolysis is down regulated when enough ATP is present in cells.
22. Allosteric regulation
• Fructose 1,6- bisphosphatase-1 (FBPase1)
– Inhibited by AMP, when energy currency ATP is less
– Thus there gluconeogenesis is down regulated because it is a energy
consuming process.
– The opposing effect of PFK-1 and FBPase-1 helps to regulate glycolysis
and gluconeogenesis according to current need of cell
23. Hormonal Regulation
• hormonal regulation of glycolysis and gluconeogenesis is mediated by
fructose 2,6-bisphosphate.
• F2,6-BP binds to allosteric site on PFK-1 increases that its affinity for
substrate F 6-P, & reduces its affinity for the allosteric inhibitors ATP
and citrate.
•PFK-1 is virtually inactive in the absence of F2,6-BP
•F2,6-BP activates PFK-1 and stimulates glycolysis in liver
•F2,6-BP inhibits FBPase-1 slowing gluconeogenesis.
24. Hormonal Regulation
• F2,6-BP formed by phosphorylation of fructose 6-phosphate,
catalyzed by phosphofructokinase- 2 (PFK-2), and is broken down by
fructose 2,6- bisphosphatase (FBPase-2).
PFK-2 and FBPase-2 are
•two distinct enzymatic activities of a single, bifunctional
Protein, which is regulated by glucagon and Insulin
Glucagon [cAMP]
increases Protein
Kinase A
Phosphorelat
ion of
enzyme
FBPase-2
Activity
Stimulate
Glyconeogenesis
26. • CREB
– Glucagon causes cAMP to rise during fasting.
– Epinephrine acts during exercise or stress.
– cAMP activates protein kinase A, which phosphorylates CREB that
stimulate transcription of the PEPCK
– Increased synthesis of mRNA for PEPCK results in increased synthesis
of the enzyme PEPCK
– Cortisol also induces PEPCK.
– Insulin stimulates inactivation of TF of PEPCK, FBTase and Glucose 6 –
phosphatase
Transcriptional Regulation
27. • FOXO1
• Forkhead box other -1
• Stimulates synthesis of
gluconeogenic enzymes
• Suppresses the synthesis of
enzymes of glycolysis, pentose
phosphate pathway,
triacylglycerol synthesis
• Insulin phosphorelate FOXO1
there by inhibiting the
gluconeogenesis. Glucogon
prevents this phosphorylation
and FOXO1 remains active in
the nucleus
Transcriptional Regulation
FOXO
1
FOXO
1 P
P
Binds with
activators
Insulin
binds
Inactive
28. • ChREBP
• A TF. Carbohydrate response element binding protein
• Dephosphorelated by phosphoprotein phosphatase 2A.
Xylulose 5-phosphate an intermediate in pentose posphate
pathway activates PP2A
• Acticated ChREBP joins with Mlx a parter protein and binds
with ChoRE
• Turns on:
– Pyruvate kinase
– Fatty acid synthase complex
– Acetyl –CoA carboxylase
Transcriptional Regulation
29. • SREBP-1c
• A TF. A member of family of sterol response element binding
proteins.
• Turns on:
– Pyruvate kinase
– Hexokinace IV
– Lipoprotein lipase
– Acetyl-CoA carboxylase
– Fatty acid synthase complex
• Turns off:
– Glucose 6- phosphatase
– PEP Carboxykinase
– FBPae-1
Transcriptional Regulation
30. Reference
• Michael M.Cox, David L. Nelson. Principles of
Biochemistry, Fifth Edition. W.H. Freeman and
Company
• Berg.M.J, Tymoczko.l.John, Stryer.L. Biochemistry,
Fifth Edition, W.H. Freeman and Company
• Voet.D., Voet.G.J, Biochemistry, Fourth Edition,
John Wiley and Sons, INC.
• Smith.C., Marks.D.A, Lieberman.M., Mark’s Basic
Medical Biochemisty A clinical Approach, Second
Edition, Lippincott Williams and Wilkins