biochem_mod2

• LIPIDS: AMPHYPATHIC
• CHOLESTEROL
• SPHINGOLIPIDS - SPINGOMYELIN (SP), GANGLIOSIDES
• GLYCEROL PHOSPHOLIPIDS - PHOSPHATIDYLCHOLINE (PC), PE, PG, PS, PI, CL

• PROTEIN:
• INTEGRAL
• PERIPHERAL

• CARBOHYDRATE: NEVER FREE
• GLYGOPROTEIN
• GLYCOLIPID

• MICELLES:
• SMALL <20 nm
• SINGLE HYDROPHOBIC TAIL

• LIPID BILAYERS:
• LARGE
• 2 FATTY ACYL CHAINS
• NON-COVALENT INTERACTIONS
• HYDROPHOBIC INTERACTIONS ARE PRIMARY FORCE, ALSO VDW & ELECSTAT

• LIPID BILAYER ~50 nm
• USED TO GET WATER SOLUBLE DRUGS PAST MEMBRANE AND INTO CELLS
• INCORPORATE INTO MEMBRANES, DIRECT DELIVERY BYPASSES CIRCULATION AND DIGESTION

SPAN MEMBRANES WITH ALPHA HELICES (HYDROPHOBIC AAs)

• CHANNEL PROTEINS FORMED BY BETA SHEETS (PORIN)
• HYDROPHOBIC AAs ON OUTSIDE
• HYDROPHILIC AAs ON INSIDE

• INTEGRAL MEMBRANES DO NOT HAVE TO SPAN ENTIRE BILAYER
• PROSTAGLANDIN H2 SYNTHASE-1 --> ARACHIDONIC ACID. ASPRIN INHIBITS

DRUGS USED TO DISRUPT IONIC GRADIENTS IN INVADING MICROORGANISMS

SMALL MOLECULES THAT SURROUND IONS AND SHUTTLE THEM ACROSS MEMBRANES

ex. VALINOMYCIN BINDS K+

1) DNA TRANSCRIBED INTO RNA WHICH IS TRANSLATED INTO PROTEIN

2) mRNA IS READ 1 CODON (3 NUCLEOTIDES) AT A TIME BEGINNING WITH AUG (METHIONINE) AND ENDING WITH STOP CODON (UAA, UAG, UGA)

3) READ 5' TO 3' AND PROT IS SYNTHESIZED FROM N TO C TERMINUS

4) mRNA UPSTREAM OS START CODON CALLED 5' UNTRANSLATED REGION (UTR) AND DOWNSTREAM CALLED 3' UTR. 5' CAP AND POLY-A TAIL

5) SEQUENCE BEGINNING WITH START CODON AND ENDING WITH STOP CALLED (ORF). EUK USUALLY HAVE ONLY 1 ORF BUT USES POST-TRANSLATIONAL PROCESSING TO MAKE SEVERAL PROTEINS

6) BASIC COMPONENTS OF TRANSLATION ARE THE RIBOSOME AND tRNA

1) CODON = 3 NUCLEOTIDE RESIDUES

2) 64 CODONS: 61 FOR AAs AND 3 STOPS

• 3) DEGENERATE: MORE THAN 1 CODON FOR SPECIFIC AA
• MORE THAN 1 tRNA FOR GIVEN AA
• DIFFERENT tRNA CARRIES INITIATOR METHIONINE (tRNAi^MET) THAN METHIONINES FOR REST OF ORF

4) SPECIFIC: EACH CODON SPECIFIES ONLY 1 AA

5) ALMOST UNIVERSAL IN ALL ORGANISMS

6) EACH NUCLEOTIDE IS PART OF ONLY 1 CODON AND ORF IS READ CONTINUOUSLY WITHOUT PUNCTUATION

ACTIVATION OF AAs

AA-tRNAs CATALYZE COVALENT LINKING OF EACH AA TO ITS tRNA

20 OF THESE ENZYMES; ONE FOR EACH AA

ANTICODON AND PROOFREADING ABILITY OF SYNTHETASE ENSURES SPECIFICITY

ATP DRIVES REACTION

AA + ATP + AA-tRNAs -------> AA-AMP + PPi + tRNA ------> AA-tRNA + AMP

SPECIAL tRNA DIRECTS ADDITION OF FORMYL GROUP (H-C=O) ONTO METHIONINE FROM N¹⁰-FTHF

3 IFs (1, 2, 3) CATALYZE FORMATION OF PRE-INITIATION COMPLEX THAT INCLUDES fMET~tRNA, mRNA, AND GTP

ANTICODON IN FIRST tRNA HYDROGEN BONDS TO AUG

SHINE-DELGARNO SEQUENCE (AGGAGG ON mRNA) H-BONDS WITH COMPLEMENTARY 16S rRNA WITHIN 30S SUBUNIT

GTP HYDROLYZED, IFs RELEASE, 50S SUBUNIT JOINS FORMING THE INITIATION COMPLEX

fMET-tRNA MOVED TO P SITE OF 70S SUBUNIT

1) SPECIAL tRNA LIKE IN PROK, BUT MET IS NOT FORMYLATED. MET-tRNA BINDS WITH GTP AND eIF-2 FORMING TERNARY COMPLEX

2) FORMATION OF INITIATOR tRNA-RIBOSOME COMPLEX. MET-tRNA-eIF-2-GTP BINDS WITH 40S SUBUNIT CONTAINING MORE eIFs

3) mRNA BINDS TO INITIATION COMPLEX. eIF-4 BINDS TO CAP SITE AT 5' END OF mRNA RESULTING IN BINDING OF eIF-4A & B. NOW 40S PRE-INITIATION COMPLEX

4) FORMATION OF 80S INITIATION COMPLEX. 40S MOVES ALONG 5'UTR UNTIL ENCOUNTERS FIRST AUG (PROCESS CALLED SCANNING; PROKS JUST USE S-D SEQUENCE). GTP HYDROLYZED, BOUND IFs RELEASED ALLOWING 60S TO JOIN. MET-tRNA IN P SITE

5) RECYCLING OF eIF-2. eIF-2-GDP CONVERTED BACK TO eIF-2-GTP BY eIF-2B. eIF-2B REQUIRED AND IS A TARGET FOR REGULATION

REGULATION OF eIF-2 ACTIVITY

SYNTHESIS OF GLOBIN CHAIN IS INHIBITED IN THE ABSENCE OF HEME

INHIBITION ACHIEVED BY ACTIVATION OF PROTEIN KINASE WHICH PHOSPHORYLATES eIF-2, PREVENTING INITIATION OF PROTEIN SYNTHESIS

IRON ANEMIA SYMPTOMS: EXTREME FATIGUE, SHORTNESS OF BREATH, HEADACHES, DIZZINESS, INFECTION, ARRHYTHMIA

SMALL PROTEINS WITH ANTI-VIRAL & ANTI-CANCER PROPERTIES

PHOSPHORYLATES eIF-2 WHICH INACTIVATES PROTEIN BIOSYNTHESIS

ACTIVATES ENDONUCLEASE THAT DEGRADES mRNA

EF-Tu AND EF-G

EUK EF-1 & 2 CORRESPOND TO PROK EF-Tu AND EF-R

• PLACEMENT OF AA-tRNA:
• EF-1 ALPHA BINGS NEXT AA-tRNA AND MOVES INTO A-SITE OF RIBOSOME

GTP HYDROLYZED TO BIND AA-tRNA ONTO A-SITE; EF-1 ALPHA-GDP COMPLEX RELEASED

EF-1 BETA GAMMA CATALYZES RECYCLING OG EF-1 ALPHA-GDP TO FORM EF-1 ALPHA-GTP IN PREPATATION TO PARTICIPATE IN THE NEXT CYCLE

• PEPTIDE BOND FORMATION:
• OCCURS BETWEEN CARBOXYL GROUP OF FIRST AA AND AMINO GROUP OF AA AT THE A-SITE, FORMING A DIPEPTIDE-tRNA WHICH REMAINS AT THE A-SITE

FORMATION OF BOND CATALYZED BY PEPTIDYLE TRANSGERASE, A RIBOSOME COMPONENT

• MOVEMENT OF PEPTIDYL-tRNA FROM A-SITE TO P-SITE:
• EF-2-GTP COMPLEX BINDS TO RIBOSOME AND STIMULATES TRANSLOCATION OF DIPEPTIDYL-tRNA FROM A TO P-SITE

RIBOSOME MOVES SO THAT NEXT CODON IS ALIGNED WITH A-SITE

EMPTY OR DEACYLATED tRNA MOVES TO E-SITE

GTP IS HYDROLYZED TO GDP AND EF-2-GDP COMPLEX IS RELEASED

REPEAT

• CYCLOHEXIMIDE
• ELONGATION

• RICIN
• TRANSLATION - MULTIPLE SITES

• PUROMYCIN: BOTH EUK & PROK
• PEPTIDE TRANSFER
• RESEMBLES 3' END OF AA-tRNA AND LACKS REACTIVE CORBONYL GROUP
• COMPETES FOR A-SITE

• ERYTHROMYCIN
• TRANSLOCATION

• NEOMYCIN
• TRANSLATION - MULTIPLE SITES

• STREPTOMYCIN
• INITIATION; ELONGATION
• RESEMBLES F-fMET-tRNA AND COMPETES FOR RIBOSOME

• TETRACYCLIN
• AA-tRNA BINDING

• PUROMYCIN: BOTH EUK & PROK
• PEPTIDE TRANSFER
• RESEMBLES 3' END OF AA-tRNA AND LACKS REACTIVE CORBONYL GROUP
• COMPETES FOR A-SITE

CORYNEBACTERIUM DIPTHERIAE SECRETES TOXIN CONTAINING ENZYME THAT ENTERS CELLS. ENZYME CATALYSES REACTION LINKING ADP RIBOSE TO EF-2, THUS INHIBITING PROTEIN SYNTHESIS.

FEVER, COUGHING, BREATHING PROBLEMS, DIFFICULTY SWALLOWING, BLOODY NOSE

GIVE IM OR IV ANTITOXIN AND FOLLOW WITH PENICILLIN AND/OR ERYTHROMYCIN

eEF-R TRANSFERES PEPTIDYL-tRNA FROM A-SITE TO P-SITE

1) TRANSLATION OF SIGNAL PEPTIDE OR SIGNAL SEQUENCE AT EH AMINO TERMINUS

2) SIGNAL RECOGNITION PARTICLE (SRP), A PROTEIN-RNA COMPLEX, RECOGNIZES SIGNAL SEQUENCE

3) SRP DIRECTS POLYRIBOSOME TO ER AND INTERACTS WITH DOCKING PROTEIN

4) TRANSLATING POLYRIBOSOME CONTINUES TO SYNTHESIZE PROTEIN WHICH WILL ENTER THE LUMEN OF MEMBRANE, WHILE RIBOSOME RECEPTOR WHICH IS LOCATED IN THE ER MEMBRANE WILL MAINTAIN THE POLYSOME DOCKED AT THE ER MEMBRANE

5) SIGNAL PEPTIDE REMOVED BY SIGNAL PEPTIDASE. THUS, SECRETED PROTEINS AND THOSE PRESENT IN TE MEMBRANE OR ORGANELLES DO NOT HAVE SAME AMINO TERMINUS AS mRNA CODING SEQUENCE

6) PROTEIN INSIDE ER PACKAGED WITHIN SECRETORY VESICLE AND MOVED TO GOLGI

7) EXTENSIVE MODIFICATION OF PROTEINS CAN OCCUR IN ER, GOLGI, AND TRANSPORT VESICLES. PROTEINS TARGETED TO THE LYSOSOMES REQUIRE ADDITIONAL MODIFICATIONS.

8) PROTEINS DESTINED FOR SECRETION END UP IN SECRETORY VESICLES THAT FUSE WITH PLASMA MEMBRANE AND EMPTY CONTENTS OUTSIDE CELL

9) PROTEINS DESTINED TO RESIDE IN PLASMA MEMBRANE END UP IN VESICLES THAT FUSE WITH PLAMA MEMBRANE, BUT MAINTAIN THE PROTEIN IN MEMBRANE

10) ENZYMES TRAVELING TO LYSOSOMES ACQUIRE MANNOSE-6-PHOSPHATE THAT ARE RECOGNIZED BY M-6-P RECEPTOR. M-6-P RESIDUES ASSIST IN TARGETING THESE PROTEINS WITHIN THEIR VESICLES TO THE LYSOSOMES

DISORDER OF PROTEIN TARGETING - INCLUSION BODIES

DEFICIENCY IN GlcNAc-1-P-TRANSFERASE ENZYME LEADING TO AN ABSENCE OF MANOSE-6-PHOSPHATE RESIDUES ON SEVERAL LYSOSOMAL ENZYMES

LYSOSOMAL PROTEINS ARE NOT DELIVERED FROM THE GOLGI TO THE LYSOSOMES

LYSOSOMAL ENZYMES WHICH NORMALLY DEGRADE WASTE PROTEINS IN THE LYSOSOME ARE SECRETED FROM THE CELL, RESULTING IN INCREASE IN SERUM LEVELS OF ENZYME. SECRETED ENZYMES GET DEGRADED.

ON OTHER HAND, CELLS DO NOT DEGRADE WASTE PRODUCTS IN THEIR LYSOSOMES, LEADING TO BUILD-UP OF INCLUSION BODIES (I-CELLS)

POST-TRANSCRIPTIONAL MODIFICATION

ADDITION TO HISTONES CHANGES INTERACTION WITH DNA (RELEASES)

GENE ACTIVATION

APL

POST TRANSCRIPTIONAL MODIFICATION

BLOOD CLOTTING PROPERTIES, INCLUDING PROTHROMBIN AND FACTOR X

CONVERSION OF GLUTAMIC ACID TO GAMMA-CARBOXYGLUTAMIC ACID

GAMMA-CGA RESIDUES NECESSARY FOR THESE PROTEINS TO BIND

HEMOPHILIA

POST-TRANSCRIPTIONAL MODIFICATION

LINKS CARBOHYDRATES AND PROTEINS TO MAKE GLYCOPROTEINS

CONTROLS TRANSFER OF PROTEINS FROM ROUGH ER TO GOLGI AND SECRETORY VESICLES

CYSTIC FIBROSIS - AUTOSOMAL RECESSIVE

ELECTROLYTE TRANSPORT IN LUNG, PANCREASE, AND LIVER DEFECTIVE CAUSING THICK MUCOUS SECRETION LEADING TO CHRONIC OBSTRUCTIVE LUNG DISEASE AND PERSISTENT INFECTION

MEMBRANE GLYCOPROTEIN, CF TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) NOT PROPERLY GLYCOSYLATED DUE TO DELETION OF 3 NUCLEOTIDES CODING FOR PHE 508, CAUSING PROTEIN MISFOLDING AND DEGRADATION WITHIN PROTEOSOMES

POST-TRANSCRIPTIONAL MODIFICATION

SPECIFIC PROLINE AND LYSINE RESIDUES IN COLLAGEN, RESULTING IN STABILIZATION OF COLLAGEN MOLECULE

POST-TRANSCRIPTIONAL MODIFICATION

HISTONES

POST-TRANSCRITIONAL MODIFICATION

HISTONES AND NUMEROUS PTOTEINS/ENZYMES

POST-TRANSCRIPTIONAL MODIFICATION

ADDITION OF A PRENYL GROUP ANCHORS THE PROTEIN ONTO CELL MEMBRANES

ASSIST IN PROTEIN FOLDING

MIS/UNFOLDED PROTEINS TEND TO AGGREGATE AND MAY BECOME EITHER RESISTANT OR SUSEPTIBLE TO DEGRADATION

NEURODEGENERATIVE DISORDERS: CDJ, ALZ, HD

INSULIN MADE BY CLEAVAGE OF PREPROINSULIN

FAMILIAL HYPERPROINSULINEMIA - EQUAL AMOUNTS OF INSULIN AND ABNORMAL PROINSULIN RELEASED INTO CIRCULATION. NEITHER DIABETIC NOR HYPOGLYCEMIC

DEFICIENCY IN PROCESSING ENZYMES OR MUTATION IN CLEAVAGE SITE OF PROINSULIN

GLUT1 - ALL MAMMALIAN TISSUES. BASAL GLUCOSE UPTAKE

GLUT2 - LIVER AND PANCREATIC BETA CELLS. IN PANC REGULATES INSULIN, IN LIVER REMOVES EXCESS GLUCOSE FROM BLOOD

GLUT3 - ALL MAMMALIA TISSUES. BASAL GLUCOSE UPTAKE

GLUT4 - MUSCLE AND FAT CELLS. AMOUNT IN MUSCLE PLASMA MEMBRANE

GLUT5 - SMALL INTESTINE. INC IN ENDURANCE TRAINING; PRIMARILY A FRUCTOSE TRANSPORTER

ENERGY SOURCE

PROVIDES LIPID PRECURSORS

FIRST GLYCOLYTIC REACTION IS ALSO FIRST STEP IN GLYCOGEN SYNTHESIS

ENERGY

FIRST REACTION NEEDED FOR FIRST STEP IN GLYCOGEN SYNTHESIS

ENERGY

LIPID PRECURSER

ALMOST ABSOLUTE REQUIREMENT FOR ENERGY

LIPID PRECURSOR

ABSOLUTE REQUIREMENT FOR ENERGY

STARCH FROM PLANTS AND GLYCOGEN FROM ANIMALS

SALIVARY AND PANCREATIC ALPHA-AMYLASE DEGRADE CARBS INTO DISACCHARIDES MALTOSE, ISOMALTOSE, AND LARGER MALTOTRIOSE, AND LIMIT DEXTRINS

SMALL INTESTINE BRUSH BORDER ENZYMES LACTASE, SUCRASE, AND GLUCOSIDASES DEGRADE MONOSACCHARIDES INTO GLUCOSE, GALACTOSE, AND FRUCTOSE

FRUCTOSE IS HIGHER IN LUMEN THAN ENTEROCYTE, AND HIGHER IN ENTEROCYTE THAN BLOOD

PASSIVELY TRANSPORTED BY GLUT5 (INTO ENTEROCYTE) AND GLUT2 (INTO BLOOD)

CONCENTRATIONS ARE LOWER IN LUMEN

RELY ON SGLT1 (SODIUM GLUCOSE TRANSPORTER 1) AND USES Na GRADIENT

GRADIENT MAINTAINED BY Na/K PUMP ON THE CAPILARY SIDE OF MEMBRANE

THEN PASSIVELY TRANSPORTED INTO BLOOD BY GLUT2

GLUCOSE + HEXOKINASE + ATP --> GLUCOSE-6-PHOSPHATE

GLUCOSE-6-PHOSPHATE + PHOSPHOGLUCOSE ISOMERASE --> FRUCTOSE-6-PHOSPHATE

FRUCTOSE-6-PHOSPHATE + PHOSPHOFRUCTOKINASE + ATP --> FRUCTOSE 1,6 BISPHOSPHATE

FRUCTOSE 1,6 BISPHOSPHATE + ALDOLASE --> GLYCERALDYHIDE-3-PHOSPHATE (GAP) OR DIHYDROXYACETONE PHOSPHATE (DHAP)

TRIOSEPHOSPHATE ISOMERASE INTERCONVERTS DHAP AND GAP

GLYCERALDEHYDE-3-PHOSPHATE (GAP) + GAP DEHYDROGENASE + NAD + Pi --> 1,3 BISPHOSPHOGLYCERATE (1,3 BPG) + NADH + H

1,3 BPG + PHOSPHOGLYCERATE KINASE + ADP --> 3-PHOSPHOGLYCERATE + ATP

3-PHOSPHOGLYCERATE + PHOSPHOGLYCERATE MUTASE --> 2-PHOSPHOGLYCERATE

2-PHOSPHOGLYCERATE + ENOLASE --> PHOSPHENOLPYRUVATE

PHOSPHENOLPYRUVATE + PYRUVATE KINASE + ADP --> PYRUVATE + ATP

ADIPOSE AND MUSCLE USE GLUT4 WHICH IS STIMULATED BY INSULIN, THUS INCREASING INTRACELLULAR GLUCOSE AND INCREASING GLYCOLYSIS

1) HEXOKINASE IS INHIBITED BY GLUCOSE-6PHOSPHATE (NEGATIVE FEEDBACK)

ex IF PFK-1 AND/OR PYRUVATE KINASE ARE INHIBITED THEN GLUCOSE-6-PHOSPHATE IN MUSCLE WILL INCREASE AND INHIBIT HEXOKINASE AND GLUCOSE UTILIZATION.

OCCURS UNDER FASTING CONDITIONS. FATTY ACIDS OR KETONE BODY OXIDATION USED FOR ENERGY SO GLUCOSE SPARED FOR RBC's

2) GLUCOKINASE IN LIVER PHOSPHORYLATES GLUCOSE WHEN BLOOD [ ] IS HIGH

WHEN [ ] REDUCED, PHOSPHORYLATION IN LIVER WILL DECLINE AND GLUCOSE UTILIZATION DECLINES. SPARED FOR RBC's

GK HAS LOWER AFFINITY FOR GLUCOSE THAN HEXOKINASE

LIVER GK IS ACTIVATED BY GLUCOSE - MOVES GK FROM INACTIVE NUCLEAR POOL TO CYTOSOL WHEN [ ] IS HIGH

LIVER GK INDUCED BY INSULIN

PFK-1 IS RATE LIMITING STEP IN GLYCOLYSIS

1) ALLOSTERICALLY INHIBITED BY ATP, CITRATE, AND PROTONS MEANING ENERGY NEEDS ARE MET

USED FOR FED AND FASTING STATE. IN FED STATE, SLOWS GLUCOSE UTILIZATION WHICH PREVENTS EXCESS FAT PRODUCTION. IN FASTING STATE, ATP AND CITRATE INCREASED DUE TO FATTY ACID OXIDATION AND TISSUES LIKE LIVER AND MUSCLE DON'T NEED GLUCOSE, THUS SPARED FOR RBC'S

2) ALLOSTERICALLY ACTIVATED BY AMP MEANING ENERGY NEEDS ARE NOT MET

ACTIVATED BY F2,6-P2 - IMPORTANT REGULATOR BECAUSE PRODUCTION IS HORMONALLY REGULATED. IN FASTING STATE, GLUCAGON DECREASES PRODUCTION OF F2,6-P2 CAUSING INHIBITION OF LIVER GLYCOLYSIS. GLUCAGON ACTIVATES ADENYLATE CYCLASE, WHICH PRODUCES cAMP WHICH DECREASES F2,6-P2 WHICH INHIBITS GLYCOLYSIS

F2,6-P2 REGULATED BY DUAL ENZYME. WHEN PHOSPHORYLATED (FASTING, GLUCAGON) F2,6-P2 IS DECREASED AND VIS VERSA (FED, INSULIN) WHEN KINASE ACTIVITY IS ACTIVATED. OPPOSITE IN MUSCLE (EPINEPHRINE)

PK INHIBITED BY ATP AND ALANINE IN LIVER AND MUSCLE (ENERGY NEEDS MET BY FATTY ACIDS AND GLUCONEOGENESIS IS UNDERWAY). SPARE GLUCOSE FOR RBC's

IN LIVER NOT MUSCLE, PK IS PHOSPHORYLATED AND INACTIVATED BY PKA WHEN BLOOD GLUCOSE IS LOW. PKA ACTIVATED BY cAMP. WHEN BLOOD GLUCOSE IS HIGH, INSULIN STIMULATES A PHOSPHATASE THAT DEPHOSPHORYLATES PK AND ACTIVATES IT.

RBC's REQUIRE 2,3-BPG TO REGULATE OXYGEN BINDING TO HEMOGLOBIN

1,3-BPG + 2,3-BPG MUTASE --> 2,3-BPG

2,3-BPG + 2,3-BPG PHOSPHATASE --> 3-PHOSPHOGLYCERATE

SIDESTEP OF GLYCOLYSIS PATHWAY BYPASSES ATP-GENERATING STEP

PRESENT IN INCREASING AMOUNTS IN WESTERN DIET

LIVER POSSESSES SPECIFIC FRUCTOSE-PHOSPHORYLATING ENZYME FRUCTOKINASE WHICH GENERATES FRUCTOSE 1-PHOSPHATE. LIVER FRUCTOLYSIS BYPASSES REGULATED PFK-1 STEP CAUSING UNDESIRED CONSEQUENCES

GALACTOSE + GALACTOKINASE --> GALACTOSE 1-PHOSPHATE

GAL 1-PHOS + GAL 1-PHOS URIDYL TRANSFERASE + UDP-GLUCOSE --> UDP GALACTOSE

UDP-GAL + GLUCOSE 1-PHOS --> UDP GLUCOSE

GLUCOSE 1-PHOSPHATE + PHOSPHOGLUCOMUTASE --> GLUCOSE 6-PHOSPHATE

GLYCEROL + GLYCEROL KINASE --> GLYCEROL PHOSPHATE

GLYCEROL PHOSPHATE + GLYCEROL PHOS DEHYDROGENASE --> DHAP

PYRUVATE KINASE DEFICIENCY IMPACT RBC's

• TUMOR CELLS PREFER GLUCOSE AND USE HYPOXIA INDUCIBLE FACTORS (HIF) TO INCREASE
• GLYCOLYSIS.

BLOCKING THIS EFFECT WILL LEAD TO SUPPRESSION

DEFICIENT GK RESULTIS IN ACCUMULATION OF GALACTOSE IN BLOOD (GALACTOSEMIA). ALDOSE CONVERTS TO GALACTITOL, WHICH IS OSMOTICALLY ACTIVE AND DAMAGES EYES LEADING TO CATARACTS

• DEFICIENT URIDYL TRANSFERASE CAUSES ACCUMULATION OF GAL 1-PHOS WHICH IS TOXIC.
• FAILURE TO THRIVE, LIVER DAMAGE, CATARACTS, AND MENTAL IMPAIRMENT

AVOIDING GALACTOSE HELPS, BUT IF DEFICIENT UT THEN MENTAL IMPAIRMENT STILL SEEN

DEFICIENCY OF ALDOSE B

BLOCKS METABOLISM OF FRUCTOSE 1-PHOS (F1-P) AND ACCUMULATION TIES UP Pi DECREASING LEVELS OF ATP

DEGRADATION OF AMP CAN WORSEN GOUT

F1-P PROMOTES GLYCOLYSIS IN LIVER, AND HIGH [ ] IS TOXIC CAUSING LIVER DAMAGE/FAILURE AND THUS HYPOGLYCEMIA

FRUCTOSE BYPASSES PFK-1 REGULATION

LARGE AMOUNTS LEAD TO FAT

F1-P ACCUMULATES LEADING TO ALDOLASE B DEFICIENCY (INCREASED GLYCOLYSIS)

MEET IMMEDIATE ENERGY AND BIOSYNTHETIC NEEDS & STORE THE REST FOR LATER

PANCREAS (BCELLS) --> INSULIN --> GLUCOSE IN LIVER TO GLYCOGEN (GLYCOGENESIS) AND TO PYRUVATE (GLYCOLYSIS) --> FAT (LIPOGENESIS)

• LIVER GLUCOSE --> BRAIN
• --> ADIPOSE TISSUE
• --> MUSCLE (MAY STORE AS GLYCOGEN)
• --> RBC's

AMINO ACIDS IN LIVER --> PROTEIN AND PYRUVATE. AA's ALSO RELEASED TO ALL TISSUES FOR PROTEIN SYNTH

LACTATE FROM MUSCLES AND RBC's RETURN TO LIVER AND CONVERTED BACK TO PYRUVATE

CHYLOMICRONS FROM GUT (TAGs + PROTEINS) --> LYMPHATICS --> TISSUES --> GLYCEROL + FREE FATTY ACIDS (FFAs) --> ACETYL CoA (BETA OXIDATION) IN MUSCLE

CALL ON ENERGY STORES TO MEET NEEDS esp BRAIN AND RBCs

PANCREAS --> GLUCAGON --> LIVER --> GLYCOGEN --> GLUCOSE --> BRAIN, RBCs, MUSCLE

CORI CYCLE. RBCs AND MUSCLE --> LACTATE --> LIVER --> GLUCOSE (GLUCONEOGENESIS)--> TISSUES

ALANINE CYCLE. PROTEINS IN MUSCLE --> ALANINE --> LIVER (GLUCONEOGENESIS)

LIVER GLYCOGEN DEPLETED IN A FEW HOURS --> "OVERNIGHT FAST"

GLUCONEOGENESIS IS ENERGY SOURCE FOR BRAIN & RBCs

CORI AND ALANINE CYCLES CONTINUE

ADIPOSE --> TAGs --> FFA (LIPOLYSIS) --> LIVER --> FATTY ACIDS BETA OXIDATION

GLYCEROL ALSO RELEASED BY TAGs --> LIVER --> GLUCONEOGENESIS

LIVER PROTEIN BROKEN DOWN --> LACTATE & AAs --> GLUCOSE (GLUCONEOGENESIS)

MUSCLE PROTEOLYSIS --> GLUTAMINE --> NUCLEOTIDE SYNTH FOR RAPIDLY DIVIDING CELLS --> ALANINE --> LIVER (GLUCONEOGENESIS)

TCA CYLE BACKS UP --> ACETYL CoA CONVERTED INTO KETONE BODIES (KETOGENESIS) --> BRAIN & MUSCLE. SPARE GLUCOSE FOR RBCs

<0, EXERGONIC & SPONTANEOUS

>0, ENDERGONIC & NON-SPONTANEOUS

/\G = /\G^ + RTLn (PROD/REACT)

/\G^ = -RTLn(Keq)

• Keq: IF > 1, /\G^ IS NEGATIVE
• IF < 1, /\G^ IS POSITIVE

SYNTHED AS PREPRO-PEPTIDE. PRE OR SIGNAL SEQUENCCE CLEACED IN ER

CONNECTING OF C-PEPTIDE REMOVED BY PROTEASE THAT CLEACE AT PAIRS OF BASIC AAs AS PRO-INSULIN IS PROCESSED

MATURE INSULIN STORED IN SECRETORY VESICLES WITH C-PEPTIDE AND AAs

ALL RELEASED WHEN GLUCOSE [ ] GOES UP

• SECRETION:
• 1) GLUC TRANSPORTED INTO BETA CELL BY GLUT2 AND PHOSPHORYLATED BY GLUCOKINASE. BOTH RESPOND TP CHANGES IN BLOOD GLUCOSE [ ] BECAUSE THEIR Km (Kd FOR RECEPTOR) ARE IN RANGE OF [ ] AFTER A MEAL

2) GLUCOSE METABOLISM INCREASES ATP LEVELS

3) ATP CLOSES A K+ CHANNEL

4) RESULTS IN OPENING OF VOLT-SENSITIVE Ca++ CHANNEL

5) Ca++ ENTERS CELL AND ACTIVATES KINASES WHICH PHOSPHORYLATE PROTEINS LEADING TO INSULIN RELEASE

EFFECTS MANY TISSUES, MAINLY LIVER, ADIPOSE, AND SKELETAL MUSCLE

BINDS TO SURFACE RECEPTOR AND STIMS TYROSINE PHOSPHORYLATION OF THE RECEPTOR (AUTOPHOSING TYROSINE KINASE)

CAUSES TYROSINE PHOS OF TWO TYPES OF PROTEINS: INSULIN RECEPTOR SUBSTRATES (IRS) AND Shc (ACTIVATES Ras-MAP KINASE PATHWAY: MITOGEN ACTIVATED PROTEIN KINASE PATHWAY REGULATES GENERAL GENE EXPRESSION)

IRS BINDS AND ACTIVATES PHOSPHATIDYLINOSITOL 3-KINASE (PI3-KINASE)

PI3-KINASE HAS 110 CATALYTIC SUBUNIT AND 85 REGULATORY UNIT. REG UNIT BINDS PHOSPHOTYROSINE RESIDUES OF IRS RESULTING IN ACT AT CAT SUBUNIT, WHICH MAKES INOSITOL LIPIDS, WHICH ACTIVATE ENZYMES, WHICH REGULATES METABOLIC PATHWAYS

OF THESE, Akt INC MOVEMENT OF GLUT4 GLUC TRANSPORTERS TO SURFACE OF ADIPOSE AND MUSCLE CELLS

ALSO ACTIVATES PHOSPHATASE PP-1 WHICH DEPHOSES METABOLIC ENZYMES, WHICH ACTS OR DEACTS ENZYMES

GSK-3 INHIBITED BY INSULIN, WHICH BLOCKS GLYCOGEN SYNTHESIS

LIVER: INC GLYCOLYSIS, FATTY ACID & TAG SYNTH, VLDL RELEASE, GLYCOGEN SYNTH, AND PROTEIN SYNTH. DEC GLUCONEOGENESIS, FATTY ACID OXIDATION, AND GLYCOGEN BREAKDOWN

ADIPOSE: INC GLYCOLYSIS, FATTY ACID AND TAG SYNTH, TAG UPTAKE FROM CHYLOMICRONS AND VLDL. DEC TAG HYDROLYSIS

MUSCLE: INC GLYCOLYSIS, GLYCOGEN SYNTH, AND PROTEIN SYNTH. DEC GLYCOGEN

DEC BLOOD GLUCOSE DEC INSULIN AND INC GLUCAGON SECRETION

RELEASED FROM ALPHA PANC CELLS AND TARGETS LIVER AND ADIPOSE. NO GLUCAGON RECEPTORS IN MUSCLE

GLUCAGON RECEPTOR IS A G-PROTEIN COUPLED RECEPTOR (USES GTP similar to how myosin uses atp)

WHEN GLUCAGON ATTACHES, GDP --> GTP AND ADENYLIL CYCLASE ACTIVATED, WHICH CONVERTS ATP TO cAMP

cAMP ACTIVATES PKA WHICH PHOSES METABOLIC ENZYMES AND TRANSCRIPTION FACTOR cAMP RESPONSE ELEMENT BINDING PROTEIN (CREB), WHICH REGULATES METABOLIC ENZYME GENES.

LIVER: INC GLUCONEOGENESIS, GLYCOGENOLYSIS, FATTY ACID OXIDATION. DEC GLYCOLYSIS, GLYCOGEN SYNTH, AND FATTY ACID SYNTH

ADIPOSE: INC TAG HYDROLYSIS

INC STRESS RELEASES CORTISOL WHICH LEADS TO EPI RELEASE

LIVER AND ADIPOSE: SAME AS GLUCAGON THOUGH ACTS ON DIFFERENT RECEPTOR

MUSCLE: INC GLYCOGENOLYSIS AND GLYCOLYSIS. DEC GLYCOGEN SYNTH

STEROID THAT PASSES THROUGH LIPED BILAYER AND BINDS TO TRANSCRIPTION FACTOR RECEPTOR

MAINLY INC GLUCOSE [ ] BY INC GLUCONEOGENESIS USING PRIMARILY AAs AND GLYCEROL (THINK ADDISON'S DISEASE)

REGULATES GENES FOR METABOLIC ENZYMES

LIVER: INC GLUCONEOGENESIS

ADIPOSE: INC TAG HYDROLYSIS

MUSCLE: INC PROTEOLYSIS

• PRODUCE ACETYL CoA FROM PYRUVATE
• GLUCOSE --> PYRUVATE --> OXIDATIVE PHOSPHORYLATION --> ACETYL CoA

REACTIONS BY 3 SEPARATE SUBUNITS (PYRUVATE DEHYDROGENASE COMPLEX (PDH))

PYRUVATE DEHYDROGENASE --> DIHYDROLIPOYL TRANSACETYLASE --> DIHYDROLIPOYL DEHYDROGENASE

PD REMOVES CO₂ AND TRANSFERS CARBON CHAIN TO THIAMINE PYROPHOSPHATE (TPP)

PD AND DT OXIDIZE INTERMEDIATE TO ACETATE MOIETY AND TRANSFER TO LIPOMIDE, MAKING ACETATE PORTION REACTIVE WITH CoA SO DT CAN MAKE ACETYL CoA

OXIDIZE LIPOAMIDE FOR ANOTHER ROUND BY DD --> REDUCE FAD TO FADH2 --> NADH

1) NEVER HAVE GLUCONEOGENESIS FROM ACETYL CoA

2) 1 GTP GENERATED BY SUBSTRATE LEVEL PHOS

3) NADH PRODUCED IN 3 REACTIONS; FADH2 IN 1

4) ALPHA-KETOGLUTARATE DEHYDROGENASE REACTION SAME AS PYRUVATE DEHYDROGENASE

5) MALATE DEHYDROGENASE REACTION FAVORS REVERSE DIRECTION, SO RAPID DEC OF PRODUCTS (OAA AND NADH) USED TO DRIVE FORWARD

• Cindy (citrate)
• Is (isocitrate)
• Kinky (alpha-ketoglutarte)
• So (succyinal CoA )
• She (succinate)
• F*** (fumarate)
• More (malate)
• Often (oxalate)

• FADH2 is generated from Succiante to Fumarate..
• Fumarate starts with an F.

CITRATE --> FATTY ACID AND STEROL SYNTH

ALPHA-KETOGLUTARATE --> AA SYNTH --> NEUROTRANSMITTERS

SUCC CoA --> HEME SYNTH

MALATE --> GLUCONEOGENESIS

OAA --> AA SYNTH

• CINDY (citrate synthase --> citrate)
• AND (aconitase --> isocitrate)
• IZZY (isocitrate dehyd --> oxalosuccinate)
• INTIMATELY (isocitrate dehyd --> alpha-ketogluterate)
• ADVERTISE (alpha-keto dehyd --> succ coa
• SENSUAL (succ coa synth --> succ
• SEX (succ dehyd --> fumarate)
• FOR (fumarase --> malate)
• MONEY (malate dehyd --> oaa)

ALPHA-KETOGLUTERATE <-- GLUTAMATE <-- AAs

SUCC CoA <-- PROPIONYL CoA <-- VALINE AND ISOLEUCINE

FUMARATE <-- AAs

OAA <-- ASPARTATE

AAs --> PYRUVATE --> OAA & ACETYL CoA

PDH AND TCA INHIBITED WHEN ENERGY CHARGE INSIDE CELL IS HIGH

ALLOSTERIC MODULATION -- PHOS INACTIVATES PDH

CALCIUM (+) (THINK MUSCLE CONTRACTION)

INSULIN (+) PDH IN ADIPOSE FOR de novo FATTY ACID SYNTH

EPINEPHRINE (+) PDH IN MUSCLE

NADH & ACETYL CoA (-) PDH

SUCC CoA (-) CITRATE SYNTH

ATP (-) AND ADP (+) ACONITASE

Ca++ (+), NADH, SUCC CoA, AND GTP (-) ALPHA-KETO DEHYD

INHIBITS TRANS-ACETYLASE SUBUNIT OF PDH AND ALPHA-KDH BY FORMING ADDUCT WITH LIPOAMIDE.

TREAT WITH BRITISH ANTI-LEWISITE (BAL)

LOWERS ACIVITY OF PDH AND ALPHA-KDH SUBUNITS

LEADS TO BERI-BERI

IMPACTS NERVOUS SYSTEM; Severe lethargy and fatigue, together with complications affecting the cardiovascular, muscular, and gastrointestinal systems.

RELY ON GLYCOLYSIS ENDING IN LACTIC ACID DUE TO INABILITY OF OXIDIZE PYRUVATE

LACTIC ACIDOSIS

NEURO DEFECTS (NO GLUCOSE FOR BRAIN)

TREAT: GENERATE KETONE BODIES IN LIVER (BRAIN AND MUSCLE CAN USE). KETOGENIC DIET HIGH IN PROTEIN AND FAT

THE FORCE THAT DRIVES THE ELECTRON FLOW

MEASURED IN VOLTS

OXIDATION-REDUCTION POTENTIAL IS THE FACILITY WITH WHICH AN ELECTRON DONOR (REDUCTANT) GIVES UP ELECTRONS TO THE ACCEPTOR (OXIDENT)

/\G = -nF/\E

OR

/\G* = -nF/\E*

n = # ELECTRONS TRANFERED

E = REDUCTION POTENTIAL IN VOLTS

F = 23

THE MORE NEGATIVE THE E*, THE GREATER THE TENDENCY TO LOSE ELECTRONS (STRONG REDUCTANT). GETS OXIDIZED. MORE POSITIVE = ACCEPT ELECTRONS (STRONG OXIDANT)

OUTER - PERMIABLE TO ANIONS AND SMALL MOLECULES

INNER - IMPERMIABLE TO EVERYTHING; CONTAINS INNER MATRIX WHERE ATP GENERATED. PROTEIN COMPLEXES OF ELECT TRANS CHAIN AND ATP SYNTHASE LOCATED IN INNER MEMBRANE. NADH ACCEPTED BY ETC IN MATRIX OR FROM FLAVOPROTEINS IN MEMBRANE

INTERMEMBRANE SPACE - BETWEEN INNER AND OUTER

COMP I (NAPDH DEHYD) - NADPH BINDS TO FMN AND PASSES 2 e- TO IT; 2 PROTONS FORCED INTO INTERMEMBRANE SPACE. THEN PASSES 2 e- TO IRON-SULFUR CLUSTERS FORCING 4 PROTONS INTO INTERMEM.

COENZ Q - PASSES 2 e- TO COMPLEX III AND MORE e- TRANSPORTED

• COMP III --> Cyt C --> COMP IV (CYT OXIDASE) AND MORE e- TRANSPORTED.
• COMP IV HAS 2 COMPLEXES IN ORDER TO REDUCE O2 (NEED 4 e-, 4 H+ TO COMPLETE)

COMP II (SUCC DEHYD) - NO PROTONS TRANSLOCATED. e- --> UQ (COENZ Q) --> COMP III

PROTONS DRIVEN THROUGH C RING CAUSING ROTATION OF GAMMA SUBUNIT

ROTATION CHANGES T STATE (BOUND ATP) TO O STATE AND ATP IS RELEASED

MEANWHILE, L FORM WITH ADP AND Pi IS CONVERTED TO T STATE (ADP --> ATP)

SUBUNIT IN O STATE CONVERTED TO L STATE WHICH BINDS ADP AND Pi

REGULATES RATE AT WHICH ENERGY IS REMOVED FROM PROTON GRADIENT IN MITOCHONDRIA.

CONTROLLED BY ADP CONCENTRATION

ELECTRON TRANSPORT CANNOT PROCEED IF PROTONS ARE NOT PUMPED INTO INTERMEMBRANE SPACE, SO IN ORDER TO KEEP SYSTEM FROM LOCKING UP, GRADIENT IS DISIPATED TO KEEP ETC GOING.

• GLYCEROPHOSPHATE SHUTTLE:
• 2 e- FROM CYTOSOLIC NADH --> DIHYDROACETONE PHOSPHATE --> GLYCEROL 3-PHOSPHATE WHICH CROSSES OUTER MITO-MEMBRANE --> FLAVOPROTEIN DEHYD --> FADH --> ETC --> 1.5 ATP

• MALATE-ASPARTATE SHUTTLE:
• CYTOSOLIC NADH REDUCES OXALOACETATE TO MALATE WHICH ENTERS MITO-MATRIX USING MALATE/ALPHA-KETOGLUTERATE. MALATE OXIDIZED BACK TO OXALOACETATE AND NADH --> ETC --> 2.5 ATP

ROTENONE - INSECTICIDE THAT INHIBITS COMP I

ANTIMYCIN A AND MYXOTHIAZOLE - NON-COMPETITIVE INHIBITS COMP III

CYANIDE AND AZIDE - REVERSIBLE INHIBITORS OF COMP IV

MALONATE - COMP II COMPETITIVE INHIBITOR (SUCC DEHYD)

RATE OF ET CAN NO LONGER BE REGULATED BY CHEMOSTATIC GRADIENT

FCCP

DNP

DISSIPATE PROTON GRADIENT (FAT SOLUABLE SO GRAB PROTONS AND DIFFUSE ACROSS MEMBRANE)

• PATHOLOGICAL UNCOUPLERS:
• SALICYLATE - DEGRATIVE PRODUCT OF ASPRIN

OLIGOMYCIN - BLOCKS PROTON CHANNEL

TREAT WITH UNCOUPLERS

AMOUNT OF ADP ADDED TO THE AMOUNT OF O2 CONSUMED

ALSO INDICATES NUMBER OF ATP MADE PER PAIR OF e-

• NADH = 2.5
• FADH = 1.5

KEARNS-SAYRE SYNDROME

MYCLONUS EPILEPSY WITH RAGGED-RED FIBERS (MERRF)

LEBER'S HEREDITARY OPTIC NEUROPATHY (LHON)

MITO ENCEPHALOPATHY LACTIC ACIDOSIS WITH STROKE-LIKE EPISODES (MELAS)

MUSCLE WEAKNESS, HEART FAILURE/ RYTHM DISTURBANCES, DEMENTIA, MOVEMENT DISORDERS, STROK-LIKE DISORDERS, DEAFNESS, BLINDNESS, VOMITING, SEIZURES

AKA HEXOSE MONOPHOSPHATE SHUNT

PROVIDES NADPH

PROVIDES 5-CARBON SUGARS

• REACTIONS REQUIRING NADPH:
• FATTY ACID BIOSYNTHESIS
• CHOLESTEROL BIOSYNTHESIS
• NT
• NUCLEOTIDE

ADRENAL GLAND - STEROID SYNTHESIS

LIVER - FATTY ACID, CHOL SYNTH

TESTES - STEROID

ADIPOSE - FATTY ACID SYNTH

OVARY - STEROID SYNTH

MAMMARY GLAND - FATTY ACID SYNTH

RBC - MAINTENANCE OF REDUCED GLUTATHIONE

• GLUCOSE-6-PHOS + G-6-P DEHYD --> 6-PHOSPHOGLUCONO-GAMMA-LACTONE + NADPH
• RATE LIMITING STEP; INDUCED BY INSULIN

6-PG-g-L + LACTONASE --> 6-PHOSPHO-GLUCONATE

6-PG + 6PG-DEHYD --> RIBULOSE 5-PHOSPHATE (NUCLEOTIDE SYNTHESIS)+ NADPH

3,4,5,7 CARBON INTERMEDIATES

ENDS IN FRUCTOSE-6-PHOS AND GLYCERALDEHYDE-3-PHOS (GLYCOLYTIC INTERMEDIATES

BERI-BERI - TRANSKETOLASE USES THIAMINE PYROPHOSPHATE AS CO-FACTOR (INHIBITED)

LACK OF NADPH LEADS TO INCREASED HYDROXYL FREE RADICAL AND OXIDATIVE DAMAGE

CANNOT REDUCE GLUTATHIONE

HEMOGLOBIN MOST SENSITIVE - HEMOLYTIC ANEMIA IF ENVIR OXIDANTS PRESENT. PLUS SIDE, SOME RESISTANCE TO MALARIA

SYNTH OF GLUCOSE FROM NON-CARB PRECURSORS (LACTATE, PYRUVATE, SOME AAs, GLYCEROL)

LIVER AND LESSER EXTENT KIDNEY

PROVIDE GLUCOSE TO RBC, BRAIN, SKEL MUSCLE

• 1) PYRUVATE CARBOXYLASE
• 2) PHOSPHOENOLPYRUVATE CARBOXYKINASE (PEPCK)
• THESE 2 ENZYMES CONVERT PYRUVATE TO PEP

• 3) F-1-6-BTASE CONVERTS F1-6B TO F6-B
• 4) GLUCOSE 6-PHOSPHATASE CONVERTS G6-P TO GLUCOSE (NON-GLUCONEOGENESIS TISSUES (LACK THIS ENZYME)