biochem_mod4_ms1

M - MITOSIS

G0 - NONDIVIDING

G1 - GROWTH, CYCLIN D, Cdks 4 & 6,

S - DNA REPLICATION, CYCLIN E

CYCLIN A, Cdk 2

G2 - PREP FOR CELL DIVISION, CYCLIN B, Cdk 1

PROGRESSION THROUGH CELL CYCLE REQUIRES CYCLIN PROTEINS, OF WHICH THERE ARE AT LEAST 20 AND CLASSIFIED INTO A,B,D, OR E

UNDERGO SEQUENTIAL BINDING TO A GROUP OF CYCLIN DEPENDENT KINASES (CDks) THROUGHOUT CELL CYCLE FORMING SPECIFIC CYCLIN-Cdk COMPLEXES

CYCLIN-Cdk COMPLEXES PHOS A DNA BIND PROTEIN CALLED RETINOBLASTOMA GENE PRODUCT (pRb)

PHOSED pRb RELEASES TRANSCRIPTION FACTOR (eg E2F

E2F STIMS TRANSCRIPTION OF GENES ENCODING ENZYMES NEEDED FOR DNA SYNTH

BIND TO CELL SURFACE RECEPTORS

STIM TYROSINE PHOSPHORYLATION AND ACTIVATING CELLULAR PHOS CASCADE

PROTO-ONCOGENES ARE GENES WHOSE PRODUCTS FUNCTION AS REGULATORS OF NORMAL CELL PROLIFERATION OR SURVIVAL

MUTATIONS IN PROTO-ONCOs GIVE RISE TO ONCOGENES WHICH EXHIBIT INAPPROPRIATE ACTIVITIES

PROTO-ONCOs CODE FOR WIDE VARIETY OF PROTEINS SUCH AS GROWTH FACTORS, GF RECEPTORS, HORMONE RECEPTORS, CELL SIGNALING MOLECULES, TRANSCRIPTION FACTORS, AND CELL CYCLE REGULATORS

GROWTH FACTORS (Sis)

GROWTH FACTOR RECEPTORS (Erb-B2)

HORMONE RECEPTORS (RARa)

CELLULAR SIGNALING MOLECULES (Abl & Ras)

TRANSCRIPTION FACTORS (Myc)

CELL CYCLE REGULATORS (CYCLIN D, Cdk 4

PLATELET-DERIVED GROWTH FACTOR

Sis

OVER EXPRESSION

• ASTROCYTOMA
• OSTEOSARCOMA

EPIDERMAL GROWTH FACTOR RECEPTOR

Erb-B2

AMPLIFICATION

MULTIPLE CANCERS

RETINOID RECEPTOR

RARa

TRANSLOCATION

ACUTE PROMYELOCYTIC LEUKEMIA (APL)

TYROSINE KINASES, Abl, TRANSLOCATION, CHRONIC MYELOID LEUKEMIA (CML) /

GTP BINDING PROTEINS, Ras, POINT MUTATION, MULTIPLE CANCERS

...

Myc

TRANSLOCATION LEADING TO BURKITT LYMPHOMA

AMPLIFICAITON LEADING TO NEUROBLASTOMA

...

CYCLIN D - TRANSLOCATION LEADING TO LYMPHOMA. AMPLIFICATION LEADING TO BREAST & LIVER CANCERS

Cdk 4 - AMPLIFICATION LEADING TO GLIOBLASTOMA. POINT MUTATION LEADING TO MELANOMA

SIGNALING MOLECULE WHICH BINDS GTP

NORMALLY REGULATED/INACTIVATED BY HYDROLYZING GTP TO GDP

ACTIVE FORM STIMS PHOS OF SERIES OF CYTO AND NUC PROTEINS LEADING TO CELL PROLIFERATION

MUTATION CAUSES PROLIFERATION EVEN IN ABSENSE OF GROWTH FACTORS (DESTRUCTION OF GTPase PRESENT IN Ras)

MULTIPLE CANCERS SUCH AS COLON, LUNG, PANCREASE, THYROID AS WELL AS LEUKEMIAS

ErbB ONCOGENE IN AVIAN LEUKEMIA VIRUS WHICH CODES FOR TRUNCATED VERSION OF EGF RECEPTOR

LOSS OF EXTRACELLULAR LIGAN BINDING DOMAIN LEADS TO PERMINANT ACTIVATION IN THE ABSENCE OF EGF GROWTH FACTOR

ONCOGENE CARRIED WITHIN VIRAL GENOME

VIRUS INSERTS NEXT TO CELLULAR PROTO-ONCOGENE LEADING TO UP OR DOWN REGULATION OF EXPRESSION

eg TRUNCATED EGF RECEPTOR

RETINOBLASTOMA (pRb) BINDS EF2, KEEPING IT FROM STIMULATING TRANSCRIPTION OF GENES ENCODING ENZYMES NEEDED FOR DNA SYNTH

p53 IS A TRANSCRIPTION FACTOR THAT CAUSES PRODUCTION OF PROTEINS THAT INHIBIT CELL CYCLE, STIM DNA REPAIR, AND CAUSE APOPTOSIS

UPON DNA DAMAGE, p53 ACTIVATES p21 WHICH INHIBITS Cdks LEADING TO INHIBITION OF CELL CYCLE, INCREASED DNA REPAIR ENZYMES AND PROTEINS THAT PROMOTE APOPTOSIS

CHEMO USING DNA DAMAGING AGENTS WORK BETTER IF p53 IS PRESENT

TRANSCRIPTION FACTOR FROM TUMOR SUPPRESSING GENE

WT-1 INHIBITS SYNTH OF GROWTH FACTOR OR GROWTH FACTOR RECEPTOR IS MUTATED

PRODUCTS OF TUMOR SUPPRESSING GENES INVOLVED IN DNA REPAIR

TUMOR SUPPRESSING GENE ATM IS DEFICIENT, THUS p53 NOT STIMULATED TO REPAIR DNA DAMAGE

INHIBITORS OF Cdks MADE FROM TUMOR SUPPRESSING GENES

MANY CANCERS, INCLUDING MELANOMA, LUNG, AND PANC, INKs (eg INK 4) IS MISSING OR MUTATED

MOSTLY IN LIVER AND MUSCLE

MOST CONCENTRATED IN LIVER BUT MORE TOTAL IN MUSCLE

REQUIRES UDP-GLUCOSE TO ADD GLUCOSE TO GROWING GLYCOGEN CHAIN

• UDP-GLUCOSE PHOSPHORYLASE REACTION:
• GLUCOSE 1-PHOS + UTP --> UDP-GLUCOSE

GLUCOSE 1-PHOS GENERATED BY PHOS-GLUC-MUTASE FROM GLUC-6-PHOS

NEED AT LEAST 11 LINEAR RESIDUES FIRST

THEN BREAK AN a1,4 LINK AND TRANSFER TO A #6 INTERNAL C

• LIVER
• CONVERTS G-1-P TO G-6-P VIA PHOS-GLUC-MUTASE. THEN G-6-P TO GLUC VIA G-6-PHOSPHATASE FOR USE IN OTHER TISSUES

• MUSCLE:
• DOES NOT RELEASE GLUCOSE (LACKS G-6-PHOSPHATASE).
• G-1-P TO G-6-P VIA PHOS-GLUC-MUTASE THEN GLYCOLYSIS

PROTEIN CORE OF GLYCOGEN POLYMER

#1C OF FIRST GLUCOSE ATTACHED COVALENTLY TO HYDROXYL OF TYROSINE ON GLYCOGENIN. USES UDP-GLUCOSE

GLYCOGEN SYNTHASE THEN TAKES OVER AFTER INITIAL RESIDUES ARE ADDED

GLYCOGEN PHOSPHORYLASE STOPS AT 4TH GLUCOSE FROM BRANCH POINT

DEBRANCHING ENZYME TRANSFERASE REMOVES 3 GLUC FROM BRANCH AND MOVES TO MAIN STRAND

a1,6-GLUCOSIDASE BREAKS THE 1 BRANCHING GLUCOSE

1) GLUCAGON & EPI INC cAMP, WHICH ACTIVATES PKA. PKA PHOSES GLYCOGEN PHOSPHORYLASE KINASE (ACTIVATION), WHICH PHOSES GLYCOGEN PHOSPHORYLASE (ACTIVATION).

3) PKA ALSO INHIBITS PROTEIN PHOSPHORYLASE, KEEPING ENZYMES ACTIVE

4) INSULIN INHIBITS GLYCOGEN PHOSPHORYLASE KINASE AND GLYCOGEN PHOSPHORYLASE BY ACTIVATING PROTEIN PHOSPHATASE

• 5) LOCAL ALLOSTERIC CONTROL:
• Ca++ ACTIVATES PHOSPHORYLASE KINASE
• AMP ACTIVATES PHOSPHORYLASE
• GLUCOSE INHIBITS PHOSPHORYLASE

WHEN MUSCLES FIRST CONTRACT, INC Ca++ AND AMP SIGNAL NEED FOR ENERGY

1) GLUCAGON & EPI INHIBIT SYNTHESIS BY PHOS OF GLYCOGEN SYNTHASE

2) Ca++ INHIBITS SYNTHESIS BY ACTIVATING CALMODULIN KINASE, WHICH PHOSES GLYCOGEN SYNTHASE

3) INSULIN ACTIVATES PHOSPHOPROTEIN PHOSPHATASE WHICH INC GLYCOGEN SYNTHASE. INHIBITS GLYCOGEN SYNTHASE KINASE (GSK) --> INC GLYCOGEN SYNTHASE

• 4) ALLOSTERIC CONTROL:
• GLUC-6-PHOS INC GLYCOGEN SYNTHASE

PHOSES REGULATORY PROT G CAUSING PROT PHOSPHATASE TO DISSOCIATE FROM G AND LOSE ACTIVITY

PKA ALSO PHOSES INHIBITOR PROT I CAUSING IT TO BIND AND FULLY INACTIVATE PHOSPHATASE

INSULIN REVERSES BY CAUSING DEPHOS OF G CAUSING REJOINING OF G AND ACTIVATION

HYPOGLYCEMIA - LIVER/KIDNEYS CAN'T RELEASE GLUCOSE

HYPERLIPEMIA AND KETOSIS - FATTY ACID MET IS INCREASED

BLOOD PYRUVATE AND LACTATE INC BECAUSE FLOOD GLYCOLYSIS WITH GLUC-6-PHOS

NEED TO PROVIDE GLUC

CERTAIN AMOUNT OF GLYCOGEN GETS INTO LYSOSOMES

NORMALLY a1,4 GLUCOSIDASE DEGRADES

IF DEFICIENT, LYSOSOME BECOMES ENGORGED WITH GLYCOGEN RESULTING IN TOXICITY

• III
• DEBRANCHING ENZYME DEFICIENCY, THE GLUCOSIDASE

CANNOT FULLY MET GLYCOGEN

• IV
• BRANCHING ENZYME DEFECT. GENERATION OF LONG GLYCOGEN POLYMERS DAMAGE HEPATOCYTES

PHOSPHORYLASE DEFECTS

McARDLE'S - INITIAL EXERCISE IS INHIBITED, INDICATED BY HIGH MUSCLE ADP (CAN'T GENERATE ATP EFFICIENTLY). DEMONSTRATES REQUIREMENT OF MUSCLE GLYCOGEN AT BEGINNING OF EXERCISE. BODY ADJUSTS THROUGH BLOOD-BORNE GLUCOSE RELEASE

• 1) SUCC-CoA + GLYCINE + ALA SYNTHASE --> ALA ACID
• MITOCHONDRIA AND RATE LIMITING STEP

• 2) 2 ALA ACIDS + ALA DEHYDROGENASE --> PORPHOBILINOGEN (CONTAINS PYRROLE RING)
• CYTOSOL

3) 4 PORPHOBILINOGEN + UROPORPHYRINOGEN I SYNTHASE --> HYDROXYMETHYLBILANE. BREAKS DOWN TO TOXIC UROPORPH I. MUST FURTHER CONVERT

4) HYDROXYMETHYLBILANE + UROPORPHYRINOGEN III COSYNTHASE --> UROPORPHYRINOGEN III. FLIPPING ONE PYRROLE RING DURING CYCLIZATION MAKES URO III INSTEAD OF URO I

• 5) URO III + URO DECARB --> COPROPORPHYRINOGEN III.
• ALL ACETYL GROUPS DECARBED INTO METHYL GROUPS. COPROPOR MOVES INTO MITOCHONDRIA

• 6) COPROPOR III + COPROPOR OXIDASE --> PROTOPORPHYRINOGEN IX.
• 2 PROPIONYLS CONVERTED TO VINYL (CH=CH2)

• 7) PROTOPORPHYRINOGEN IX + PROTOPOR OXIDASE --> PROTOPORPHYRIN IX.
• DOUBLE BONDS IN RINGS MOVE BETWEEN SIDE CHAINS.

8) PROTOPORPHYRIN IX + FERROCHELATASE --> HEME. Fe ADDED TO RING

1 FOUND IN NON-ERYTHROID CELLS

2 IN ERYTHROIDS

A) Fe INDUCES HEME SYNTHESIS. 5'UTR OF mRNA FOR ALA 2 HAS SEGMENT WHICH BINDS Fe-BINDING PROTEIN (STABILIZES), BUT ONLY WHEN Fe IS PRESENT

B) EXCESS HEME INHIBITS Fe UPTAKE. DIETARY Fe TRANSPORTED IN BLOOD BY TRANSFERRIN (LIGAND FOR RECEPTOR LETTING Fe INTO CELL). HEME INHIBITS (A)

C) HEME AND GLOBIN ARE BALANCED. HEME INHIBITS A KINASE THAT ACTS ON eIF2. eIF2 THUS UNPHOSED AND INC GLOBIN SYNTH.

GLOBIN COMBINES WITH HEME, SO HEME [] DROPS, THUS PHOSING eIF2 AND INHIBITING GLOBIN SYNTH

A) HEME INHIBITS TRANSPORT OF ALA SYNTHASE 1 INTO MITOCHONDRIA (MAJOR CAUSE)

B) HEME INHIBITS SYNTH OF ALA SYNTHASE 1

C) HEME ALLOSTERICALLY INHIBITS ALA (NOT PHYSIOLOGICALLY IMPORTANT...?) SYNTHASE 1

HEME DEGRADATION AND IMMUNE SYSTEM

MACROPHAGES, MONOCYTES, AND KUPFFER CELLS IN LIVER

RE ISOZYME OF HEME OXIGENASE INDUCED BY HEME, TIN, COBALT, OR STRESS

ASIDE FROM RE ISOZYME, 2 OTHERS IN BRAIN AND TESTES

C0 AS BYPRODUCT

FAMILY OF DISEASES WHICH ARISE FROM LESIONS IN HEME BIOSYNTH PATHWAY

CAUSED BY ACCUMULATION OF INTERMEDIATES

NO PORPHYRIAS CAUSED BY DEFECT IN ALA SYNTHASE GENE

ALA SYNTHASE PORPHYRIA

RARE

LESIONS IN ALA SYNTHASE

NOT ENOUGH HEME --> LESS HEME FEEDBACK CONTROL OF ALA SYNTHASE --> HIGH ALA SYNTHASE

VERY RARE

ABDOMINAL AND NEUROLOGICAL

BUILD-UP OF dALA

VERY SUSCEPTIBLE TO LEAD POISONING

PORPHOBILINOGEN DEAMINASE

ONE OF MOST FREQUENT

LESSENED ACTIVITY OF PB DEAMINASE RESULTING IN INC PB AND dALA

ABDOMINAL AND NEUROLOGICAL

SOME PSYCHOSIS

UROPOR-GEN III COSYNTHASE

VERY RARE

ACCUMULATION OF UROPOR-GEN I, UROPORPHYRIN I, COPOR-GEN I, AND COPROPORPHYRIN I

PHOTOSENSITIVITY, DISCOLORED URINE, PIGMENTS IN TEETH

UROPORPHYR-GEN DECARB

MOST COMMON

ACCUMULATION OF UROPORPHYRIN III

SYMPTOMS LARGELY IN SKIN

MAY BE INDUCED BY HEXACHLOROBENZENE

TREAT WITH CHLOROQUIN AND PHLEBOTOMY

COPROPOR-GEN OXIDASE

RARE

ACCUMULATION OF COPROPORPHYRIN III

NEUROLOGICAL AND ABDOMINAL

SOMETIMES INVOLVES SKIN

PROTOPORPHYRINOGEN OXIDASE

ACCUMULATION OF SEVERAL PORPHYRINS

SKIN LESSIONS

SOME ABDOMINAL AND NEUROLOGICAL

FERROCHELATASE

PHOTOSENSITIVITY

ACCUMULATION OF PORPHYRINS IN SKIN

SOME SYMPTOMS OF PORPHYRIA

SOME ENZYMES IN HEME SYTH INHIBITED BY LEAD (dALADEHYDE AND FERROCHELATASE)

ENZYMES HAVE SULFHYDRYL GROUPS THAT REACT WITH HEAVY METALS

ABDOMINAL - BUILD-UP OF TOXIC INTERMEDIATES AND BY-PRODUCTS IN LIVER CAUSE PAIN

NEUROLOGICAL - BUILD-UP IN BRAIN CAUSES PSYCH BEHAVIOR AND/OR NEURO SYMPTOMS

SKIN - BUILD-UP IN SKIN, REACTIONS WITH ULTRA-VIOLET LIGHT MAKE FREE RADICALS

TEETH - BUILD-UP CAUSES DISCOLORATION AND BRITTLE TEETH

CERTAIN TYPES AGGRAVATED BY CERTAIN DRUGS SUCH AS PHENOBARBITAL

INDUCE LIVER TO MAKE CYTOCHROME P450 WHICH CONTAINS HEME, AND MAKE HEME ITSELF

ACCUMULATION OF TOXIC INTERMEDIATES

MUST PROPERLY DIAGNOSE PATIENT BEFORE TREATMENT

SYMPTOMS DUE NOT APPEAR UNTIL PUBERTY

INC SEX HORMONES AND INCREASE ACTIVITY/AMOUNT OF ENZYMES (CYTOCHROME P450)

PUBERTY INDUCES HEME SYNTH WHICH CAUSES ACCUMULATION IN THOSE WITH LESIONS IN HEME SYNTH PATHWAYS

EXCESS ERYTH DESTRUCTION

HIGH BIL-ALB, HIGH EXCRETION

LIVER DAMAGE SO LESS REACTION OF BILIRUBIN WITH GLUCURONOSIDE

HIGH BIL-ALB, LOW BIL EXCRETION, LOW BIL-GLUCURONIDE

IMMATURE LIVER

SIMILAR BILIRUBIN METABOLISM TO CIRRHOSIS AND HEP

TEMPORARY

TREAT WITH UV RAD TO DESTROY EXCESS BIL

HIGH BIL-ALB, LOW EXCRETION

RARE JAUNDICE

COMPLETE LOSS OF UDP-GLUCUNOSYLTRANSFERASE ACTIVITY

BIL DISTRIBUTION SIMILAR TO CIRRHOSIS AND HEP, BUT MORE EXTREME

FATAL IF LEFT UNTREATED

UV RAD FOR TREATMENT OR LIVER TRANSPLANT

HIGH BIL-ALB, LOW EXCRETION

JAUNDICE

UDP-GLURUNOSYLTRANSFERASE ACTIVITY DOWN 90%

ENCEPHALOPATHY IF UNTREATED

TREAT WITH PHENOBARBITAL - INDUCES UDP-GLURUNOSYLTRANSFERASE SYNTHESIS

JAUNDICE

UDP-GLURUN-ASE ACTIVITY IS DOWN 50%

BEGNIGN CONDITION & IN 10% OF POPULATION

TREAT WITH PHENOBARBITAL

JAUNDICE

OBSTRUCTION PREVENTS BILE FROM REACHING INTESTINE

BIL-GLUCURONOSIDE IS HIGH, BIL-ALB NORM, EXCRETION LOW