BMB402 Metabolism and Nucleotides

hepatic portal vein

vein that carries blood from GI tract and spleen to liver

creatine kinase

catalyzes reversible reaction interconverting ATP and phosphocreatine using ADP and creatine substrates

adipokines

peptide hormones secreted by adipose tissue that regulate metabolic homeostasis

astrocytes

glia that surrounds neurons, close contact with brain vasculature, forms BBB

PET imaging

measures metabolic activity and blood flow changes in the brain by monitoring distribution of radioactive glucose, used for tumor screening

metabolic homeostasis

maintaining optimal (metabolites) and managing chemical energy reserves and organism

thymidine

short for deoxythymidine (deoxyribonucleotide containing thymine)

thymidylate

thymidine with a 5' monophosphate

PRPP

intermediate in purine and pyrimidine synthesis and component of nucleotide salvage

uric acid

purine product of degradation of nucleotides

gout

joints and kidney disease caused by increased uric acid in blood leading to uric acid crystal formation

5-fluorouracil

imidine analog and anticancer drug that irreversibly inhibits thymidylate synthase

methotrexate

dihydrofolate reductase inhibitor and anticancer drug that stops methyl donor synthesis from dUMP to dTMP

nucleotide general structure

nucleotide base (pyrimidine and purine), ribose from PPP, and phosphoryl group

where do newly synthesized nucleotides come from?

turnover via nucleic acid degradation/recycling (less energy than de novo synthesis), all bases EXCEPT THYMINE come from RNA and some can be obtained from diet

nucleotide salvage pathway

RNA is degraded and used to generate nucleoside triphosphates to be reincorporated back into RNA

nucleotide base salvage

ribose-5-phosphate (from PPP) and free nucleotide bases are produced and attached to PRPP to make 5'-monophosphates

purine biosynthesis

base is built DIRECTLY ON SUGAR -> makes IMP intermediate -> makes AMP and GMP

pyrimidine biosynthesis

base is built then RIBOSE IS ADDED -> UMP intermediate -> makes CTP and TMP , fewer reactions since they are less complex molecules

regulation enzymes for purine biosynthesis

PRPP synthetase and glutamine-PRPP aminotransferase

inhibitors of PRPP synthetase

ADP and GDP (since the nucleotides are already made)

inhibitors of glutamine-PRPP aminotransferase

all phosphorylated forms of adenine and guanine nucleotides

pyrimidine biosynthesis regulation

1st and last steps are allosterically regulated by the need to make matching nucleotides

activators of pyrimidine biosynthesis

PRPP, ATP, GTP

inhibitors of pyrimidine biosynthesis

CTP, UTP, UDP

diseases caused by defects in purine degradation pathway

gout, lesch-nyhan syndrome, adenosine deaminase deficiency (SCID)

enzyme that turns RNA bases into DNA bases

ribonucleotide reductase - makes deoxyribonucleotides from non-T bases

activity of ribonucleotide reductase

wide-ranging, multiple active sites, balances all deoxyribonucleotides

how are T bases synthesized?

thymidylate synthase

thymidylate synthase

methylation of uracil to turn dUMP to dTMP, target of many anticancer drugs ex. methotrexate

pancreas function

secretes insulin and glucagon to change serum glucose

small and large intestine function

absorb nutrients and water, respectively

liver function

central metabolic organ, glucose regulator

four fates of glucose-6-phosphates

glycogen synthesis in liver, glucose in blood to travel to other organs, pentose phosphate pathway to make NADPH, glycolysis to make acetyl-CoA

3 metabolic fates of acetyl-CoA

acts as a principle intermediate of lipid biosynthesis, oxidative phosphorylation, and ketogenesis

enzyme that makes acetyl-CoA from pyruvate

pyruvate dehydrogenase

what does skeletal muscle use for fuel?

free AAs, glucose, ketone bodies

what muscle tissue is used for energy during starvation?

skeletal muscle

fuel during resting state if little glucose

FAs

fuel for short bursts of energy

ATP

cardiac muscle fuel

fatty acids and ketone bodies

creatine kinase

synthesizes ATP rapidly by taking a phosphate from phosphocreatine, reverses under high ATP conditions

adipose tissue

secretes adipokine peptide hormones to regulate metabolic homeostasis, makes up 15-25% of body mass

phosphocreatine function

stores "potential for ATP" in its phosphoryl group

fuel for brain

exclusively glucose under normal conditions

what metabolites are allowed to pass through bloodstream

glucose (normal) ketone bodies (starvation) not FAs

kidney function

use gluconeogenesis to synthesize glucose to export to periphery, filter and excrete urea, NH4+, ketone bodies, and more

systemic component of triacylglycerol cycle

FAs move from adipocytes to liver when bound to albumin, triacylglycerol is in lipoproteins

intracellular component of triacylglycerol cycle

interconverts FAs and triacylglycerols within adipose tissue

common intermediate for both parts of triacylglycerol cycle

glycerol-3-P to resynthesize triacylglycerol

main purpose of triacylglycerol cycle

move fatty acids and triacylglycerol where needed

cells that make insulin

pancreatic beta cells

what does insulin stimulate?

glycogen synthesis and fatty acid synthesis, glucose uptake in liver, adipose tissue, skeletal muscle

cells that make glucagon

pancreatic alpha cells

what does glucagon stimulate?

gluconeogenesis, glycogen degradation, FA export from adipose tissue

TNF-α

inflammatory cytokine produced at high levels in adipocytes when there is high lipid levels, affects insulin receptors

effect of increase TNF-α

downregulation of genes involved in lipid storage, increase in serum FAs, and decrease in insulin signaling

what direction does the replication fork move?

3' to 5'

in which direction are DNA strands built?

5' to 3'

what cofactor activates DNA polymerases?

Mg2+

klenow fragment

polymerize and edit DNA, made from cleave of DNA polymerase I

polymerizing mode of klenow fragment

nucleotides added at polymerase active site

editing mode of klenow fragment

"new nucleotide" end of strand is flipped out of the active site into the exonuclease site where it is excised from the DNA strand

which enzyme is more error prone - DNA polymerase or reverse transcriptase?

reverse transcriptase

PPAR signaling

peroxisome proliferator-active receptors in the nucleus determine lipid homeostasis and regulates gene expression of enzymes involved in lipid metabolism

Defects in PPAR signaling can cause ??

insulin sensitivity

Which processes are upregulated during starvation?

FA release, gluconeogenesis, ketogenesis, and protein degradation

DNA polymerase 1 function

proofreading, repair primer removal

DNA polymerase 2 function

repair

DNA polymerase 3 function

main polymerizing enzyme

Which DNA polymerases are needed to stay alive?

1 and 3