introduction to medical biochemistry

• macromolecules - DNA, proteins, carbohydrates, lipids
• metabolites - glucose, atp, hormones, neurotransmitters
• electrolytes - cations, anions, etc
• xenobiotics

• can form large complex structures
• chemical polymers of a set of monomers or non covalent assemblies of smaller units
• emergent properties resulting in folding and structure allows them to perform unique activities

small molecules that are intermediates in biochemical pathways or act as regulators of function

small ions present in high conc

• foreign compounds that the body must degrade or excrete before they increase in amount and cause damage to the body
• not synthesized by the body or part of normal metabolism

• F: enzymatic, structural, movement, information carrying, compartmentalization
• MA: ribosomes, membranes, chromosomes, starch, glycogen
• SMA: lipids to membranes, nucleotides to DNA, amino acids to peptides to proteins

• carbohydrates - energy, structure, immunity
• nucleotides - carry info, energy
• proteins - chemistry and structure
• membranes - compartmentalization (seperates into sides and catergories)

• metabolic syndrome disease
• congenital diseases
• vitamin deficiencies
• cancer
• cardiovascular disease

• energy 
• store energy
• attaches to lipids to form glycolipids to act as immune recognition and a physical barrier
• attaches to proteins to form glycoproteins  that help regulate folding and structural proteins

• glucose-epimer
• fructose
• galactose-epimer
• mannose-epimer

• ribose
• deoxyribose

• contains aldehyde or ketone that permits cyclization (a formation of one or more carbon/hydrogen rings)
• the central carbons are asymmetric which constitute a sterocenter (has 3 diff attachments) indicate direction the hydroxyl group is drawn (fischer projections)
• upon cyclization (formation of the ring) the 1 position carbon becomes a stereocenter, is reversible but the cycle forms are favored. the two forms of glucose are either alpha (up) or bet (down)
• most simple sugars are reducing (have a free aldehyde and ketone group) except sucrose due to linkage

• sucrose - glucose and fructose
• lactose - glucose and lactose
• **lactose intolerant due to lack of lactase**
• maltose - di-glucose (alpha 1-4)
• **results from starch/glycogen breakdown in gut**

• sucrose - fructose and glucose linked at alpha 1-2
• lactose - galactose and glucose in a beta 1-4 link
• maltose - 2 glucose molecules in a alpha 1-4 linkage same as glycogen
• maltodextrin - 3 or more linearly joined glucose units in alpha 1-4 link

Starch (amylose – linear non branched chain of glucose molecules connected by alpha1>4 glycosidic bonds, less digestible – Amylose forms more compact, less hydrated structures, and is digested much slower (fewer end points, and the more compact, less hydrated structure makes it less accessible to digestive enzymes (needs to be cooked if contained)

Amylopectin – glucose storage in plants that animals can digest. Alpha 1-4 glycosidic bonds with branch points of alpha1-6 glycosidic bonds)

Glycogen – glucose storage in animals, linear alpha 1-4 glucose chains plus branches form by alpha 1-6 glycosidic bonds

Cellulose – most abundant biomacromolecule, this is a dietary fiber. It is not digested to a significant extent in humans because we lack an enzyme to break the β(1-4) glycosidic bond, as do other mammals.

N-acetyglucosamine

n-acetygalactosamine

n-acetyl-neuraminic acid

Galactose

Fucose

Mannose

Glycolipids create carb trees attached to lipid proteins i.e blood antigens (molecule capable of inducing an immune response to produce an antibody in the host organism, the precise linkage and order depends on the individual, and recognition of those carbohydrates helps to determine if it is seen as foreign or self

modified sugar residues – n-acetyl glucosamine and glucuronic acid

polymerization

attachment to Ser residues on proteins

can be structural components and can form integral and substantial part of connective tissue

the chondroitin sulfate repeat at the end provides a lot of negative charge to sugar chains to keep them hydrates and apart providing elasticity required for connective tissue

source of E

source of AA to rebuild new proteins

movement

communication, receptor signaling

transport

structure

catalysts

product of information carried on the genome

C: Anionic: glu, asp Cationic: arg, lys, his

P: ser, thr, gln, asn, cys

NP:leu, Ile, met, val, phe, tyr, trp

S: ala glycine

Cy:Pro

Information storage – DNA

Information transfer – mRNA

Post transcriptional processing – miRNA

Translation – rRNA and tRNA

Catalytic enzymatic function

Energy transduction

Cofactors

S: ATP, GTP, CTP, UTP (deoxy forms: Datp, dgtp, dctp,dttp

C:nicotine adenine dinucleotide (NAD), flavine adenine dinucleotide (FAD), flavine mononucleotide (FMN), coenzyme A (CoA)

D/R: mrna, trna, rrna, sirna, mirna

Sugar: Ribose 5 C sugar, deoxy ribose

Base: purines 2 = adenine, guanine, pyrimidines 1=cytosine, thymine , uracil

**attaches to 1 carbon of sugars

Phosphate: forms the backbone linkage at the 5’and 3’ positions of the ribose or deoxyribose



DNA 5-3 reading, A=T G-=C, anti-parallel, same amount of AT as CG

RNA amounts of AUCG varies, will form base pairs but will be single stranded or loops, ratios of each help determine if DNA or RNA

Can be amorphous (no defined structure): mrna (long strands), sirna (small post transcription reg), mirna (micronRNA)

Have discrete structures: tRNA, rRNA

Have transient structures mrna

All carry info

Structural (ribosomes)

Catalytic (ribozymes)

Carriers (trna)

Transcriptional regulation (splicing)

Translational regulation (sirna,mirna)

Non polar or amphipathic molecules (constituents of micelles, vesicles, and bilayer sheet

Not soluble, forms micelles, vesicles, or membrane sheets and become dispersed

Constituents (part of) membranes, fats, oils, waxes, detergents

Sugar: Ribose 5 C sugar, deoxy ribose

Base: purines 2 = adenine, guanine, pyrimidines 1=cytosine, thymine , uracil

**attaches to 1 carbon of sugars

Phosphate: forms the backbone linkage at the 5’and 3’ positions of the ribose or deoxyribose



DNA 5-3 reading, A=T G-=C, anti-parallel, same amount of AT as CG

RNA amounts of AUCG varies, will form base pairs but will be single stranded or loops, ratios of each help determine if DNA or RNA

Hydrophobic liquid

Can be hydrocarbons, triglycerides, or FA of varying length but can be other chemical types of as well

tryglycrides, hydrophobic solid

Natural or synthetic amphiphilic compounds that act as surfactants

from membrane lipids in that they tend to not form bilayers, but rather form micelles. In most cases this is because the polar head group is bigger than hydrophobic acyl chain

detergents have the ability to carry hydrophobic molecules in their cores, thus effectively dissolving oils and fats.

Energy storage                

Compartmentation (division into separate parts)

Signaling molecules (steroids)

Vitamins

Dietary lipids used for heart disease

**key to lipids is their hydrophobicity

**structure polar head group, glycerol backbone, fatty acids

**middle glycerol positions contains an unsaturated fatty acid. This is typical for many lipids. The fatty acid in this position can be released in response to hormones and act as a signaling molecule or precursor

Molecules are those with polar and non polar parts and can form bilayers, vesicles, micelles

**depending on shape they are classified as detergents (form micelles) or membranous lipids – can form bilayers/monolayers as vesicles or membranes

One major class of lipids is the glycerol-phospholipids 6

They have a glycerol backbone

They have two fatty acids

The middle position (2-position) fatty acid is typically unsaturated.

The end position fatty acid may be saturated.

They have a phosphate at the other end of the glycerol

They can have a headgroup attached to the phosphate .

Ethanolamine

Choline

Serine

Inositol

 

**The headgroups defines the charge properties and the cell-signaling properties of the lipids.

In addition to constituting a major structural, lipids participate specific cell signaling events

 

 

Vesicles, or liposomes, are bilayers enclosing a limited aqueous compartment. They are typically spherically shaped, the bilayer forming the outer layer of the sphere

 

Bilayers occur in vesicles, but may also form larger, flatter sheets that constitute plasma

membranes, the endoplasmic reticulum, etc etc.Bilayers have two monolayers juxtaposed with their non-polar (hydrophobic) parts together,

and the polar parts interaction with water. To form vesicles or bilayer sheets, the lipids that constitute them must be amphipathic

is the interconversion of food, storage molecules and energy through highly regulated chemical reactions that adapt to changes in food supply and energy demands.

the conversion of complex food and storage molecules (complex carbohydrate,

protein and fat) into simpler components (monosaccharides, fatty acids, aminoacids) that

can be utilized for energy.

The use of simple metabolites (simple sugars, fatty acids and amino acids) to generate more complex molecules for storage (glycogen, triglycerides, and protein) and for maintenance and growth (new proteins, membranes), including specialized molecules such as hemes, cholesterol, and nucleotides.

Fat: tyglycerides (glycerol and 3 FA chains) (major storage not converted to glucose), located in liver and muscle as adipocytes

Protein: major storage for AA in liver and muscle, Metabolism of proteins and amino acids must include metabolic pathways for excreting nitrogenous compounds. Amino acids can be metabolized to yields glucose and E, located in muscle

Glycogen: glucose storage (24 hour supply), located in muscle and liver, available so other mechanisms for prolonged fast

stores glycogen, protein and some fat.

It functions to maintain blood levels of glucose during the fasted and stressed state and to synthesize fat from carbohydrate and amino acids during the fed state.

It is a major site of biosynthesis and processing between the intestines and other organs.

is the major storage site for protein and glycogen. Muscle lacks glucose-6-phosphatase and cannot make glucose for other organs. Because of its glycogen stores, muscle can function anaerobically for a short time.

tissue serves as the major storage site for triglycerides (FAT)

is specialized for nitrogen metabolism and the excretion of urea.

serves to absorb nutrients from digested food and pass them on to the liver and blood.

(erythrocytes) are specialized for oxygen delivery. Having no mitochondria, they rely exclusively on anaerobic metabolism for energy.

normally uses glucose for its fuel and metabolizes little fat.

During starvation or long fast, brain can adapt to use ketone bodies for fuel

Hexokinase

Phosphofructokinase

Pyruvate kinase

Has a number of important vitamins and cofactors. Deficiency in these causes

metabolic problems.

Regulates movement of pyruvate to Acetyl CoA.

Regulates by Acetyl CoA, NADH, and by phosphorylation.

Regulated indirectly by hormones

The transformation of glucose to pyruvate; generates small amount of energy quickly, takes place in cytoplasm

Breakdown of Acetyl (Acetyl CoA) to CO2 with production of reducing equivalents (NADH and CoQH2, takes place in mictochondria, energy used GTP, 3nADH, 1 FADH2, waste 2CO2, regulate substrate and cofactor

The breakdown of fatty acids to Acetyl CoA; this takes place in the mitochondria. It ultimately makes energy (ATP) from fat stores

electron transport. Converts high energy electrons (reducing power) to ATP and makes water from oxygen, takes place in mitochondria

**Note Pyruvate ends Glycolysis and is a central intermediary with several possible fates.

• Pyruvate
• Beta-oxidation of fatty acids
• Ketone bodies

• TCA cycle entry
• FA synthesis
• Ketone body production

• Serve as start points in anabolic reactions
• Serve as end points for catabolism of many amino acids
• Are involved in other pathways and transport mechanism

Lactate (anaerobic metabolism)

AcetylCoA – aerobic energy production, fatty acid synthesis

Oxaloacetate – anapleurotic reactions (refilling of TCA intermediates) or the first reaction point of gluconeogenesis (Liver glucose production)

Ethanol – in microorganisms during fermentation.

Alanine – Nitrogen transport

• TCA cycle produces reducing equivalents in the form of NADH, and CoQH2
• TCA cycle produces 1 ATP equivalent as GTP.
• TCA cycle produces 2 CO2 from Acetyl CoA.

Citrate synthase

Isocitrate dehydrogenase

Alpha-ketoglutarate dehydrogenase


**By limiting cofactors (NADH in particular)

**By ATP and ADP concentrations in the mitochondrion.

**By Mass action coupling to oxidative phosphorylation

energy (muscle and other tissues)

urea cycle, converts AA and Co2 to urea

Glucose synthesis in the liver or kidney (gluconeogenesis) during fasting

**proteins are degraded by proteases and by the proteasome (targeted degradation)

Pyruvate (glucogenic)

Acetyl CoA (ketogenic)

TCA cycle intermediates

Ketogenic – feed only into acetyle coa

Glucogenic – those that feed into pyruvate or replenish TCA cycle intermediates, can be glucogenesis precursors

Ketogenic and glucogenic – breakdown results in both acetyl coa and TCA cycle intermediates

Solar energy drives the energetics of life on the earth.

Plants use light (photons) to split water and to fix CO2

This produces:Oxygen in the atmosphere 

Stored reducing equivalents in the form of the following:

Fats, Oils,Carbohydrates,Proteins

Metabolism harvests reducing equivalents (food), and recombines them with

oxygen. This generates the energy that supports:

Temperature Biosynthesis Mechanical movement The results are water and CO2

A thermodynamic quantity that is the difference between the internal energy of a system and the product of its absolute temperature and entropy; the capacity of a system to do work, as in an exothermic chemical reaction

Dietary proteins, sugars, and fats digested in mouth stomach and intestines yiled amino acids, simple sugars and FA

Things require or taken in smaller quantities, i.e nucleotides, vitamins, etc.

• Occurs principally in the liver
• Occurs when there is sufficient carbohydrate influx to raise Acetyl CoA concentrations beyond what is needed for local energy needs.
• Acetyl CoA is turned into fatty acids and combined with glycerol phosphate to make triglycerides.
• Triglycerides are packaged into lipo-protein particles called VLDL (very low density lipoprotein).
• VLDL is exported to the circulation where it will traffic the triglycerides to adipose

tissue (when fed)

ATP from oxi phos

NADPH from hexo monophosphate shunt aka pentose phosphate pathway (can also produce ribose as ribose-5-phosphate)

Contains the enzymes for the TCA cycle, including pyruvate dehydrogenase.

Oxidative phosphorylation occurs here and includes:: Electron transport, Proton gradient, ATP synthesis

Conversion of glucose to reducing power to proton gradient to ATP –energy transduction.

Converts oxygen to H2O – O2 is the source of oxidative energy. Creates a proton electrochemical gradient

**differnce between chemical gradient –concentration & Electrical gradient –voltage.Reminder that everything has to get in and out by transport

Purpose: To maintain circulating glucose concentrations and prevent hypoglycemia during long-term fasting (>4hr). Insulin is low, glucagon high. Cortisol, epinephrine and norepinephrine may also be high. Cortisol, epinephrine, and nonepinephrine may also be high

Occurs in: The liver and kidney.

What it accomplishes: Synthesizes glucose for export to the circulation.

During fasting, insulin drops and glucagon increases. Glucagon stimulates glycogen breakdown to supply circulating glucose, and with extended fasting, will then also induce gluconeogenesis. Gluconeogenesis is the synthesis of glucose from precursors. Pyruvate is considered a start point of gluconeogenesis.Pyruvate can not be directly reversed to phosphoenolpyruvate and so goes through two other reactions:Conversion to Oxaloacetate & Conversion of Oxaloacetate to phosphoenolpyruvate The intermediate oxaloacetate is a TCA cycle intermediate and allows TCA cycle to feed into gluconeogenesis.From phosphoenol pyruvate, glycolysis is reversed until Fructose 1,6 bisphosphate, where  a separate enzyme is required to convert it to Fructose-6-phosphate. The reversal results in Glucose -6-phosphate. Another gluconeogenic enzyme,

glucose phosphatase, is required to convert G6-phosphate to glucose

lactate – anaerobic glycolytic metabolism

alanine and glutamine from protein breakdown

glycerol from fat breakdown

other products that feed into the TCA cycle

metabolite -  feed forward, feedback inhibition or activation, cofactor/substrate restrictions, allosteric protein regulation

phosphorylation – often hormone mediated (insulin generally dephosphorylates; glucagon activates protein kinase A)

changes in protein activity – changes in transcription/translation, changes in glucose transporter (delivery)

the product blocks further entry into the pathway by inhibiting the first step

high concentration of A promotes its own entry into the pathway

common in glycolysis, ATP inhibits further production of ATP whereas ADP activates the pathway to generate more ATP

Pyruvate dehydrogenase is the enzyme regulated by phosphorylation

Specific kinase can phosphorylate and inactivate PDH.

A specifici phosphatase can remove the phosphate and render PDH active.

The Kinase and phosphatase are in turn regulated by small molecule metabolites: ATP,

AcCoA, NADH, and Ca2+

**In addition, there is also more direct feedback inhibition by Acetyl CoA and

on, the glucose transporter, Glut4, is delivered from internal vesicle stores to the plasma membrane to increase glucose uptake in response to insulin stimulation