A list of string replacements in Python

Looks like a good opportunity to use a loop:

mapping = { 'A':'1', 'B':'2', 'C':'3', 'D':'4', 'E':'5'}
for k, v in mapping.iteritems():
    my_string = my_string.replace(k, v)

A faster approach if you don't mind the parentheses would be:

mapping = [ ('A', '1'), ('B', '2'), ('C', '3'), ('D', '4'), ('E', '5') ]
for k, v in mapping:
    my_string = my_string.replace(k, v)

You can easily use string.maketrans() to create the mapping string to pass to str.translate():

import string
trans = string.maketrans("ABCDE","12345")
my_string = my_string.translate(trans)

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