Amino Acids and Protein Chemistry

The vast majority of drugs used in medicine are targeted to ______

proteins (receptors, ion channels, enzymes, and transport proteins)

It is important to understand protein ______ in order to understand drug action on proteins

structure

Regardless of their function, all proteins have

similar structure and are made up of amino acid linked together in a long chain

Proteins are _______ of alpha amino acids

linear heteropolymers

______ are bifunctional

amino acids

Amino acids contain both a ______ and _____ group

basic amino group

acidic carboxyl group

____ is the smallest and simplest of all the amino acids

Glycine

glycine

Glycine is essentially ______ in terms of electronic or solubility effects

neutral

_____ has no steric hindrance and conveys flexibility to a peptide chain

glycine

Alanine

Valine

Leucine

Isoleucine

What AAs have aliphatic, lipid soluble, hydrocarbon side chain?

Alanine, valine, leucine, and isoleucine

The side chains on alanine, valine, leucine, and isoleucine are most important for forming _______ within a protein or enzyme

lipid soluble pockets

The _________ on alanine, valine, leucine, and isoleucine can either block or allow access to certain portions of a protein

varying steric bulk

Proline

______ is a unique AA that contains a secondary amine

Proline

Proline has a __________ side chain that forms an

lipid soluble hydrocarbon side chain

alicyclic ring (pyrrolidine)

What is the most important feature of proline?

The alicyclic ring produces a significant steric effect that causes protein chains to bend

Natural human proteases cannot cleave peptide bonds that include which AA?

proline

Phenylalanine

Trytophan

Phenylalanine and tryptophan contain aromatic rings and are _____ soluble

lipid

Phenylalanine and tryptophan have a greater electronic nature and can interreact with

aromatic rings on drug molecules

Tryptophan contains an indole ring which makes the ring ______ than the phenyl ring

more electron rich

Nitrogen atom in the indole can act as a

hydrogen bond donor

Serine

Threonine

Tyrosine

Phosphoserine

Serine, threonine, and tyrosine all contain

hydrozyl groups

__________ are classified as water soluble uncharged AAs

serine and threonine

_____ is an AA with aromatic rings that is more water soluble than phenylalanine

tyrosine

Why are hydroxyl functional groups important?

Due to their ability to form hydrogen bonds as both acceptors and donors

The hydroxyl groups for serine, threonine, and tyrosine are ________ so they are often _________ as part of a regulatory mechanism

nucleophiles

phosphorylated

Tyrosine phosphorylation is the addition of a

phosphoryl group (PO3)-2

Tyrosine phosphorylation is made possible through enzymes called

tyrosine kinases

______ is a key step in signal transduction and the regulation of enzymatic activity (eg cell growth)

Tyrosine phosphorylation

TK inhibitors are drugs that inhibits tyrosine kinases are typically used as

anticancer drugs (gefitinib)

Cysteine

Methionine

Homocysteine

_____ is a precursor to methionine

Homocysteine

_________ are water soluble uncharged AA

Cysteine and methionine

-SH containing AA ability to form hydrogen bonds is ______ than -OH containing AA

weaker

Cysteine and methionine are

nucleophilic

The ability of cysteine to form disulfide bonds is essential for the ________ of proteins

three dimensional confomation

Aspartic Acid

Glutamic Acid

In acidic AAs, the carboxylic acid side chain is primarily ________ (except stomach)

ionized

Aspartic and glutamic acid are ____ soluble and provide ______ for ionic interactions

water

negative charges

Asparagine

Glutamine

Asparagine and glutamine are ___ soluble and not able to be ______

water

ionized

In asparagine and glutamine, the amine groups serve as

hydrogen bond donors and acceptors

Asparagine and glutamine are not very necleophilic because

the lone pair of non bonding electrons on amide are involved in resonance

Lysine

Arginine

Histidine

Lysine and arginine are primarily _____ in all physiological environments and provide _____ for ionic interactions

ionized

positive charges

Histidine (imidazole ring) is ____ basic than lysine/arginine and is primarily _________

less

unionized

Lysine, arginine, and histidine enhance

water solubility

Histidine can act as a hydrogen bond

acceptor or donator

The carboxyl group of AA is _________ and exists as ______ at physiological pH

deprotonated

carboxylate anion

The amino group of AA is _______ and exists as the _______ at pphysiological pH

portonated

ammonium cation

AAs exist in aqueous solution primarily in the form or a

dipolar ion (Zwitterion)

________ is the pH at which a particular molecule carries no net electrical charge

Isoelectric point

For the neutral AA side chain, pI is the avaergae of

pKa1 and pKa2

The AAs with acidic chains, the pI is the average of _______

the two lowest pkA

For the AA with basic side chain, p! is the average of

the two highest pkA

A _____ bond is a chemical bond formed between two AA molecules when the carboxyl groups of one reacts with the amino group of the other and releases a molcule of water

peptide

The ____ structure of a protein is the order in which the individual AAs making up the protein are linked together through peptide bonds

primary

What are the three main secondary stuctures?

alpha helix, beta pleated sheet, and beta turn

The _______ structure is the overall 3D shape of a protein

tertiary

The _____ structure of proteins is crucial to their function and interaction with drugs

tertiary

Only proteins that are made up of a number of protein subunits have a _____ structure

quaternary

________ structure involves interactions between the exterior surfaces of proteins and it is also possible for protein molecules to interlock

quaternary

_______ is a tripeptide mimic that inhibits the angiotensin converting enzyme (ACE) and is used to treat high blood pressure

Enalaprilat

What are the four protein receptors drug targets?

Ligand gated ion channels

G protein coupled receptors

Kinase linked receptors

Nuclear receptors

Cancer drugs target _____ receptors

kinase linked

Hydrolase, isomerase, ligase/polymerase, lyase, oxidoreductase, and transferase are _______ drug targets

enzymes

Group ______ are protein therapeutics with enzymatic or regulatory activity

I

_____ replacing a protein that is deficient or abnormal

Ia

_____ augmenting an existing pathway

Ib

___ providing a novel function or activity

Ic

Protein therapuetics with special targeting activity

Group II

___ interfering with a molecule or organism

IIa

_____ delivering other compounds or proteins

IIb

Protein vaccines group

Group III

_____ protecting against a deleterious foreign agent

IIIa

_____ treating an autoimmune disease

IIIb

_____ treating cancer

IIIc

Protein diagnostics group

Group IV

How does Lispro (fast acting insulin) differ from the beta chain of human insulin?

28 - lys

29 - pro

Who does Aspart (fast acting) differ from beta chain of human insulin?

28 - asp

How does Glulisine (fast acting) differ from beta chain of human insulin?

29 - Glu

How does long lasting insulin work?

Adding AAs (glycine or asparagine) delays insulin release in body

____ is the study of the biochemical and physiologic effects of drugs

Phharmacodynmanics